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The Normal Pulmonary Vascular Transition at Birth
CONGENITAL DIAPHRAGMATIC HERNIA
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THE NORMAL PULMONARY VASCULAR TRANSITION BIRTH Robert C. Dukarm, MD, Robin H. Steinhorn, MD, and Frederick C. Morin IIt MD
It is critical to establish the foundation of the multiple processes involved in the normal pulmonary vascular transition at birth to understand its pathogenesis and pathophysiology in the infant with congenital diaphragmatic hernia. In most neonates, the normal pulmonary vascular transition occurs quickly in the delivery room. To understand this "transition/' we must realize that underlying it is the process of fetal lung development that begins several weeks after conception and is not complete until several days to weeks after birth. We will therefore review the embryogenesis of the pulmonary vasculature, including angiogenesis and vasculogenesis, as well as the possible role that growth factors, growth inhibitors, and mechanical forces have in the normal development of the pulmonary vasculature. We will also review the vasoactive substances that modulate vascular tone in the fetus. Finally, we will look at the stimuli that initiate the transition at birth and the agents that may mediate it. We have reviewed some of this material in more detail elsewhere. 74• 101
NORMAL PULMONARY VASCULAR DEVELOPMENT
Structural
There is a close association of pulmonary arterial and airway development. At week 4 of human development, an endodermal pair of lung From the Division of Neonatology (RCD, RHS, FCM), Departments of Pediatrics (RCD, RHS, FCM) and Physiology (FCM), State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, New York
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buds arise from the esophagus, surrounded by mesenchyme containing a vascular network. These vessels accompany developing airways as they differentiate into arteries, and go on to join the larger pulmonary arteries that originate from the sixth branchial arch. 4 ' 121 As gestation progresses, synchronization of airway and vessel branching occurs, 46, 47 indicating they potentially respond to common mediators or exchange messenger molecules. The veins arise separately from the loose mesenchyme of the lung septa and subsequently connect to the developing left atrium. Angiogenesis and vasculogenesis are two morphogenetic processes that contribute to the development of the pulmonary vasculature. Vasculogenesis begins with differentiation and segregation of angioblasts from mesodermal tissues. These endothelial cell precursors migrate, adhere, and form vascular channels that become arteries, veins, or lymphatics depending on local factors. Angioblasts contribute to the expression of smooth muscle phenotype in the surrounding mesenchyme, or they recruit existing smooth muscle cells (SMC) to the forming vessel. Angiogenesis, the budding or sprouting of new vessels from preexisting vessels or vascular channels, then occurs. Within the buds are distinct zones of migration, proliferation, differentiation, and basement membrane formation that result in the formation of new vessels. 21 ' 85, 88 Therefore, there are probably distinct embryonic origins for endothelial and vascular smooth muscle cells in the proximal and distal vasculature, which could account for their subsequent differences in functional behavior. 33, 127 Proliferation of endothelial cells, SMCs, and fibroblasts is necessary for continued pulmonary vascular growth. Although exact mechanisms controlling vascular growth are not known, the production of local growth factors is likely involved. Basic and acidic fibroblast growth factors (FGF), which are present in the major vessels of embryonic rats, 31 are potent angiogenic factors. 53 Blockade of the FGF receptor in a transgenic mouse model results in ablation of branching morphogenesis of the lung,84 and antibodies to the basic FGF retard vascular development.65 Basic FGF increases endothelial mRNA and protein synthesis of nitric oxide synthase, and NO production, suggesting that part of its effects may be mediated through N0. 56 Transforming growth factor-beta (TGF-[3) has also been shown to be coupled with pronounced angiogenic activity43 and to increase the production of collagens I and III and proteoglycans by lung fibroblasts. 44 Platelet-derived growth factor (PDGF) may be an important factor in vascular development and cell differentiation. Both PDGF isoforms and receptors are expressed in the developing lung,13, 41 and PDGF is mitogenic for vascular SMC and fibroblasts. 89 Insulin-like growth factor (IGF) mRNA expression has been demonstrated by in situ hybridization to be present in pulmonary arteries of the human fetus. 42 Both IGF I and II stimulate SMC and fibroblast proliferation, and they increase elastin and collagen production in neonatal pulmonary vascular walls. 8 Neonatal pulmonary artery SMC may be more sensitive to IGF I than are those from adults. 28 Although growth factors are likely important, vascular growth in the fetus also occurs
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independently of growth factors. For instance, vascular SMC isolated from fetal rat aorta replicate by mechanisms independent of growth factors, which is distinct from the adult phenotype requiring exogenous mitogens. 23 • 69 As development progresses, the embryonic endothelial channels acquire a smooth muscle layer 27 and, therefore, the ability to generate vascular tone and regulate blood flow. Structurally, pulmonary arterial SMC change during development. 40• 72 Actin and myosin, the two major contractile proteins, exist as structural isoforms whose expression is developmentally regulated. 83 As development of the vascular wall progresses, a transition occurs from the [3-nonmuscle to the smooth muscle specific a-actin isoform. 35 At least four heavy chain myosin isoforms have been identified: two smooth muscle (SM) isoforms and two nonmuscle (NM) or synthetic isoforms. 30 The expression of all four appears to be developmentally regulated in the chick embryo. 30 Increased expression of the synthetic isoforms may explain the decreased responsiveness to constrictors observed in pulmonary arteries isolated from immature sheep and piglets as compared with adult animals. 18• 63 Up to 70% of the mass of the wall of large pulmonary arteries is composed of elastin and collagen produced by smooth muscle cells. Elastin provides the vessel with distensibility, and collagen provides it with rigidity. Many of the growth factors mentioned previously are likely involved in the regulation of elastin and collagen synthesis. The majority of elastin production takes place during fetal life and essentially none occurs after the first decade. Collagen has several chemical types, whose expression varies with age. Types V and III are most abundant in the pulmonary arteries isolated from neonatal pigs. 72 During normal postnatal development expression of the high tensile strength type I collagen increases. These changes may partially explain the relatively high compliance of the neonatal circulation and the subsequent adapations that occur in the postnatal period. Mediators of High Fetal Pulmonary Vascular Tone Much of our understanding of the regulation of the fetal circulation comes from experiments done in the fetal lamb. From 85 to 145 days of gestation (term= 146 days), the number of small blood vessels increases 40-fold, whereas the wet weight of the lung increases fourfold. 64 Therefore, the number of small blood vessels per unit of lung increases 10fold. Despite this increase in the number of vessels, fetal pulmonary circulation is characterized by high arterial pressure and high vascular resistance, and pulmonary blood flow does not increase. 75 Right ventricular output instead bypasses the lungs through the foramen ovale and ductus arteriosis, and it provides blood flow to the organ of gas exchange, the placenta. In the fetus, only 5% to 10% of the combined cardiac output flows to the lungs, whereas 50% flows to the placenta. 75 • 90 Because the fetal pulmonary vascular bed responds readily to vasodila-
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Table 1. PROPOSED MEDIATORS OF PULMONARY VASCULAR TONE IN FETAL AND TRANSITIONAL CIRCULATION Vasoconstrictors (Maintain High Fetal PVR)
Vasodilators (Decrease PVR During Transition)
Norepinephrine cx-Adrenergic stimulation Hypoxia Endothelin Thromboxane Leukotrienes Platelet activating factor PGF2"
PG!,, PGD 2, PGE 2 Nitric oxide cGMP Oxygen Adenosine ATP Bradykinin
PVR = pulmonary vascular resistance; PG = prostaglandin; cGMP = cyclic guanosine monophosphate; ATP = adenosine triphosphate.
tors, 107 this high-resistance, low-flow state is probably maintained in part by vasoconstriction. Hypoxic pulmonary vasoconstriction, sympathetic tone, norepinephrine, arachidonic acid metabolites, and endothelin are potential mechanisms and mediators. to explain the high fetal vascular tone (Table 1). Although electrical stimulation and norepinephrine increase pulmonary vascular resistance in the fetal lamb,10• 14• 22 neither sympathectomy nor alpha-adrenergic blockade decreases the resistance. 10• 22 Therefore, sympathetic tone does not appear to be responsible for the high pulmonary vascular resistance of the fetus. Arachidonic acid constricts the pulmonary circulation of the fetus and newborn. no, 113 Its cyclooxygenase products, prostaglandin F2"' and thromboxane A 2 are synthesized by the fetal lung16 and are vasoconstrictors in the fetal and newborn lung. 62• 67 Blocking prostaglandin or thromboxane synthesis, however, does not decrease vascular resistance, 20• rn. n 7 suggesting that these metabolites may not be responsible for the high vascular resistance in the fetus. Leukotrienes are metabolites of arachidonic acid via the lipoxygenase pathway. Leukotriene D4 is a potent vasoconstrictor in the fetal and newborn lamb, an effect that may be mediated by thromboxane release. 100 Leukotriene receptor antagonists/ synthesis inhibitors increase fetal pulmonary blood flow manyfold, 34• 99 although this may be due to nonspecific vasodilating effects. 34 Leukotriene concentrations in the fetal lung liquid are less than concentrations that would be expected to cause vasoconstriction, 16• n 6 and production is significantly higher in adult sheep as compared with newborn and fetal sheep. 48 Therefore, additional studies are needed in this area to determine if leukotrienes are important in maintaining high fetal vascular tone. Vasoconstriction in response to low oxygen tension may contribute to high pulmonary vascular resistance in the fetus. Hypoxic pulmonary vasoconstriction develops over the period of gestation when the crosssectional area of the vascular bed is increasing rapidly. Decreasing
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oxygen tension in the fetus at 103 days of gestation does not increase pulmonary vascular resistance, but in the 132-to-138 day fetus it doubles the resistance. 64 Conversely, increasing oxygen tension before 100 days of gestation does not decrease pulmonary vascular resistance, but by 135 days it decreases resistance markedly and increases pulmonary blood flow to normal newborn levels.75 • 76 Although the mechanism by which low fetal oxygen tension regulates pulmonary vascular tone is not known, it may be in part through regulation of activity and gene expression of nitric oxide synthase71 • 81• 94 and/ or endothelin. 57 In addition, acute decreases in oxygen tension decrease prostacyclin synthesis in pulmonary arteries isolated from fetal lambs. 96 Endothelin is an endothelium-derived peptide with potent vasoconstrictor properties, and it therefore could cause high vascular tone. Three isoforms of this 21-amino acid peptide have been characterized, termed endothelin-1, endothelin-2, and endothelin-3. Endothelin is generated from a 203-amino acid peptide called preproendothelin, which is cleaved to a 92-amino acid form, big endothelin-1. Endothelin-converting enzyme cleaves big endothelin-1 to endothelin-1, which is 100 times more potent.1 25 Endothelin binds to specific ET A and the ET 8 receptors that have been cloned and characterized. 5 • 91 ET-1 binds with high affinity to the ETA receptor that is predominantly expressed in vascular smooth muscle and mediates vasoconstriction. The ET 8 receptor binds all three isopeptides with equal affinity. It is more widely distributed in cell types of various tissues, including endothelial cells. Endothelial ET 8 receptors mediate vasodilation, but recent studies propose that this receptor also mediates vasoconstriction in certain tissues, including the rabbit pulmonary artery. 115 The role of endothelin in determining fetal and transitional pulmonary vascular resistance is unclear. Intrapulmonary infusions of ET-1 transiently dilate the pulmonary vascular bed of the intact fetal lamb. 15• 19 In contrast, intrapulmonary infusions of big endothelin-1 constrict this same vascular bed,51 an effect that is reversed by phosphoramidon, an inhibitor of the endothelin-converting enzyme. Endothelin-1 constricts pulmonary arteries and veins isolated from fetal lambs. 118• 12° Furthermore, endothelin-1 infusions increase pulmonary arterial pressure in newborn lambs 123 and in fetal lambs ventilated with 100% oxygen. 15 These data indicate that the effects of exogenous endothelin are complex and depend on the site, developmental age, and tone of the vascular bed. Plasma concentrations of endothelin-1 are highest in immediate newborn piglets, and they decrease steadily in the subsequent 10 days of life. 63 Low oxygen tension, possibly by decreasing nitric oxide production, induces the expression and secretion of endothelin-1 in cultured human endothelial cells. 57 Endothelin receptor blockade, however, does not block the increase in pulmonary arterial pressure in the intact newborn lamb exposed to hypoxia, 123 and conversely it does not block the increase in pulmonary blood flow following oxygen ventilation of the fetal lamb .122
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THE TRANSITION AT BIRTH
At birth, a dramatic decrease in pulmonary vascular resistance allows half of the combined ventricular output to be redirected from the placenta to the organ of gas exchange in the newborn, the lung. This decrease in pulmonary vascular resistance leads to an 8- to 10-fold increase in pulmonary blood flow. The increase in pulmonary blood flow increases the pressure in the left atrium, which closes the one-way flap valve of the foramen ovale. Systemic vascular resistance increases at birth, at least in part due to removal of the low vascular resistance bed of the placenta. The largest immediate drop in pulmonary vascular resistance occurs at birth; however, this resistance continues to drop over the first several months of life until it reaches the low level normally found in the adult circulation. As pulmonary vascular resistance falls to less than systemic, blood flow through the patent ductus arteriosus reverses. Over the first several hours of life the ductus arteriosus functionally closes, largely in response to the increased oxygen tension of the newborn. The ductus arteriosus may not anatomically close for several months. It is critical that all of these events occur within the first several hours of life for the normal postnatal pattern of circulation to be established. The stimuli that seem to be most important in decreasing pulmonary vascular resistance are (1) ventilation of the lungs with a gas, (2) lowering carbon dioxide tension, and (3) raising oxygen tension in the lungs. Each of these stimuli by itself will decrease pulmonary vascular resistance and increase pulmonary blood flow. 87, 105 The largest effects are seen when the three occur simultaneously. Intrauterine ventilation of the fetal lamb, without changing the arterial tension of carbon dioxide or oxygen, increases pulmonary blood flow to approximately two thirds of that observed following birth. 87, 105 To study the effect of raising oxygen tension without ventilating the lung, chronically instrumented fetal lambs were studied while the ewe breathed oxygen in a hyperbaric chamber at three atmospheres absolute. 6, 45 During hyperbaric oxygenation, fetal pulmonary vascular resistance decreases and pulmonary blood flow increases to levels comparable to after birth. 75, 76, 78 Agents Mediating Transition
Prostaglandins have been proposed as important mediators of the transition at birth. Indomethacin and meclofenomate, both inhibitors of prostaglandin synthesis, blunt the decrease in pulmonary vascular resistance noted when the fetal lung is ventilated with a gas. 61 , m, 117 Whereas PGI 2 and PGD2 are fetal pulmonary vasodilators, PGI2 seems to be the prostaglandin involved in the transition. It can be quantified by measuring its stable hydrolysis metabolite 6-keto-PGF]c,. Prostacyclin and its metabolites dilate the fetal pulmonary vascular bed. 17, 5 s, 62, 109 PGI 2 synthesis in ovine PA endothelium and vascular smooth muscle in-
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creases markedly during late fetal and early newborn life. 12• 96 This increase is due to a rise in cyclooxygenase activity related to enhanced expression of cyclooxygenase-1. 12 Following birth, there is a switch from net clearance to net production of PGI 2 by the lungs. 59• 60 The effect of oxygen tension on prostaglandin production in the fetal and newborn lung is complex. Increasing oxygen tension increases PGI2 synthesis in pulmonary arteries isolated from fetal lambs 95 ; however, indomethacin does not block the increase in fetal pulmonary blood flow and decrease in pulmonary vascular resistance produced in hyperbaric chamber,78 and fetal plasma levels of the metabolite 6-keto-PGF 1a are not changed during hyperbaric oxygenation. 77 In postnatal lambs, acute hypoxia directly stimulates cyclooxygenase gene expression and PGI 2 and PGE 2 synthesis in endothelial cells and isolated lungs. 38• so. 96 Prostacyclin synthesis by the lung during hypoxia may be greater in the immediate newborn period than later in life, and it may thus provide a protective mechanism against hypoxic vasoconstriction. 36 • 37 The relative role of prostacyclin during normal transition is not certain. PGl 2 production declines within hours after birth, and the initial net production by the lungs may revert to net clearance within days after birth. 60• 73 Furthermore, the increase in pulmonary vascular resistance caused by meclofenomate sharply declines after birth, and by 12 days of age it has no hemodynamic effects. 86 Indomethacin only modestly increases pulmonary artery pressure in term lambs at birth. 25 Its effect on the transition to gas exchange by the lungs at birth is variable. 25 • 112 Activity of adenylate cyclase, the effector mechanism producing dilation to prostacyclin, decreases as the fetus approaches term. 97 This may explain why the role of prostaglandins seems to be more important in the preterm fetus. 61 The role of endothelial derived nitric oxide during fetal lung development and transition has been under intensive investigation. Nitric oxide (NO) is produced from the terminal nitrogen of arginine by nitric oxide synthase (Fig. 1). All three of the known nitric oxide synthase (NOS) isoforms are present and developmentally regulated in the fetal rat lung. 68 • 82• 124 Immunostaining for the endothelial constitutive (type III) NOS isoform in the fetal lamb lung peaks during midgestation and decreases postnatally. 39 Recent studies suggesting that NO may induce apoptotic cell death in vascular SMC 79 further support a role for NO in lung vascular development. Developmental and locational differences also exist in the functional activity of NOS. NOS activity can be demonstrated as early as 117 to 120 days' gestation in the fetal lamb. 52 Basal and stimulated release of NO from pulmonary arteries from the near term fetus appear diminished, however, when compared with the amount released postnatally.3· 66 • 102• 126 NOS function may vary with location in the vasculature. Pulmonary veins from fetal and newborn lambs release more NO than do pulmonary veins from older lambs. 102 Pulmonary veins are also more responsive to exogenous NO than are pulmonary arteries. 32• 33 • 102• 104
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Oxygen Birth Shear Stress
Acetylcholine Bradykinin
L-NA L-NMMA
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Figure 1. The proposed mechanism of synthesis and action of nitric oxide (NO). NO is produced in the endothelium from the terminal guanido nitrogen of L-arginine by NO synthase. NO synthase can be stimulated by pharmacologic agents such as acetylcholine or bradykinin, as well as by birth, shear stress, and oxygen. Endothelial production of NO can be blocked by arginine analogues that have modifications of the guanido nitrogen of the molecule. NO activates soluble guanylate cyclase, increases cGMP concentrations in vascular smooth muscle, and initiates the cascade resulting in smooth muscle relaxation. The magnitude and duration of the effect of cGMP is controlled by its inactivation by specific phosphodiesterases. cGMP = guanosine 3' ,5' -cyclic monophosphate; GMP guanosine 5' monophosphate; GTP = guanosine 5' triphosphate.
Venodilation may play an important role in producing the increased pulmonary blood flow seen normally following birth. Stimulating NO production mimics the transition by dilating the fetal pulmonary vascular bed. The pulmonary vasodilation produced by
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acetylcholine in the fetal lamb 26 can be blocked by the arginine analogues L-NA and L-NMMA and restored by excess L-arginine, indicating that acetylcholine is stimulating endothelial NOS. 2 • 107 Blocking NOS activity with the arginine analogue L-NA immediately prior to delivery of the fetal lamb blunts the increase in pulmonary blood flow and decrease in pulmonary vascular resistance following birth. 2 Furthermore, when LNA is infused into fetal lambs for 10 days prior to birth at doses that do not increase basal pulmonary vascular tone, the decrease in vascular tone and the increase in pulmonary blood flow normally seen at birth are significantly blunted in lambs, and pulmonary arterial pressure remains equal to aortic pressure. 29 Oxygen is probably an important stimulus for endothelial NO production during transition. The increased pulmonary blood flow following hyperbaric oxygenation of the fetal lamb is almost completely blocked by L-NA (Fig. 2). 108 The mechanisms for the increase in NO release related to increased oxygen tension are not clear. Both basal and stimulated release of endothelial NO increase when oxygen tension is acutely increased in pulmonary arteries isolated from late-gestation fetal lambs, 97 • 119 and NO production is attenuated following acute decreases in oxygenation in cultured fetal pulmonary arterial cells. 94 Changes in oxygen tension regulate NOS gene expression in fetal pulmonary arterial cells81 and human endothelial cells. 71 Other mechanisms may exist in
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Figure 2. Effect of hyperbaric oxygen (squares) and the L-arginine derivatives L-NMMA (circles) and L-NA (triangles) on pulmonary blood flow in fetal lambs. L-NMMA was infused following 30 minutes of hyperbaric oxygenation; L-NA was infused 30 minutes prior to hyperbaric oxygenation. Values are means ± SE. * Significantly different from period prior to hyperbaric oxygenation. t Significantly different from control group. (Adapted from Tiktinsky MH, and FC Morin Ill: Increasing oxygen tension dilates fetal pulmonary circulation via endothelium-derived relaxing factor. Am J Physiol 265:376-380, 1993, with permission.)
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vivo. For instance, bradykinin, which stimulates endothelial NO production, increases during hyperbaric oxygenation of fetal sheep 45; however, blockage of the bradykinin receptors responsible for pulmonary vasodilation does not block the response to ventilation with oxygen. 9 Oxygen increases red blood cell adenosine triphosphate (ATP), which is a fetal pulmonary vasodilator and potential stimulus for endothelial NO production. 55, 103 Infusion of purine receptor antagonists blocks the pulmonary vasodilation to oxygen in the fetal lamb. 54 Finally, NO binding to hemoglobin may be altered when it becomes fully saturated after birth.49, so Shear stress increases the synthesis of NO in the fetal pulmonary circulation. 24 In bovine, rabbit, and human aortic endothelial cells, mRNA expression and activity of endothelial constitutive NOS increase following shear stress.7· 114 The regulation of this response is complex and may involve fundamental alterations in regulation of endothelial NO synthase activity.7 During transition, an initial increase in pulmonary blood flow produced by ventilation or increased oxygen tension may increase shear stress, which then increases NO synthesis and further enhances the increase in pulmonary-blood flow. Shear stress may lead to further postnatal adaptation of the pulmonary circulation by increasing expression of 13-actin mRNA and producing cytoskeletal remodeling in endothelial cells. 70 Cyclic guanosine monophosphate (cGMP) mediates the vascular smooth muscle relaxation produced by NO. Infusions of cGMP analogues, or of atrial natriuretic factor, which stimulates cGMP production by particulate guanylate cyclase, produce prolonged dilations of the pulmonary circulation of the fetal lamb. 1 The magnitude and duration of cGMP effect is regulated by specific phosphodiesterase isoforms (PDE). 93, 106 Expression of the cGMP-specific (type V) PDE is developmentally regulated in rat lung, 92 and inhibition of cGMP phosphodiesterases dilates the pulmonary vascular bed of normal fetal lambs.11, 128 These relaxations are blocked with L-NA, suggesting they are due to enhancement of the effect of cGMP generated in response to endogenous NO. The interaction between cyclic adenosine monophosphate (cAMP) and cGMP may be also important in the transition at birth. Both nucleotides compete for clearance by type I (calcium/ calmodulin-stimulated) PDE, and cGMP inhibits the clearance of cAMP by type III PDE. 106
SUMMARY
Although the normal pulmonary vascular transition at birth takes place quickly in the delivery room, it has its basis in the complex structural and biochemical development of the lung. We are only beginning to understand the stimuli that initiate and mediate the transition, as well as their interrelationships. Comprehension of normal structure and function is the foundation that will enable us to understand how
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this process is impaired in the baby born with congenital diaphragmatic hernia. References 1. Abman SH, Accurso FJ: Sustained fetal pulmonary vasodilation with prolonged atrial natriuretic factor and GMP infusions. Am J Physiol 260:H183-H192, 1991 2. Abman SH, Chatfield BA, Hall SL, et al: Role of endothelium-derived relaxing factor during transition of pulmonary circulation at birth. Am J Physiol 259:H1921-H1927, 1990 3. Abman SH, Chatfield BA, Rodman DM, et al: Maturational changes in endotheliumderived relaxing factor activity of ovine pulmonary arteries in vitro. Am J Physiol 260 (Lung Cell Mo! Physiol 4):L280-L285, 1991 4. Adamson IYR: Development of lung structure. In Crystal RG, West JB (eds): The Lung: Scientific Foundations. New York, Raven Press, 1991, p 663 5. Arai H, Hori S, Aramori I, et al: Cloning and expression of a cDNA encoding an endothelin receptor. Nature 348:730-732, 1990 6. Assali NS, Kirschbaum TH, Dilts PV: Effects of hyperbaric oxygen on uteroplacental and fetal circulation. Circ Res 22:573-588, 1968 7. Ayajiki K, Kindermann M, Hecker M, et al: Intracellular pH and tyrosine phosphorylation but not calcium determine shear stress-induced nitric oxide production in native endothelial cells. Circ Res 78:750-758, 1996 8. Badesch DB, Lee P, Parks WC, et al: Insulin-like growth factor I stimulates elastin synthesis by bovine pulmonary arterial smooth muscle cells. Biochem Biophys Res Commun 160:382-387, 1989 9. Banerjee A, Roman C, Heyma1m MA: Bradykinin receptor blockade does not affect oxygen mediated pulmonary vasodilation in fetal lambs. Pediatr Res 36:474-480, 1994 10. Barrett C, Heymann M, Rudolph A: Alpha and beta adrenergic receptor activity in fetal sheep. Am J Obstet Gynecol 112:1114-1121, 1972 11. Braner DAV, Fineman JR, Chang R, et al: M&B 22948, a cGMP phosphodiesterase inhibitor, is a pulmonary vasodilator in lambs. Am J Physiol 264:H252-H258, 1993 12. Braimon TS, North AJ, Wells LB, et al: Prostacyclin synthesis in ovine pulmonary artery is developmentally regulated by changes in cyclooxygenase-1 gene expression. J Clin Invest 93:2230-2235, 1994 13. Buch S, Jones C, Sweezey N, et al: Platelet-derived growth factor and growthrelated genes in rat lung. I. Developmental expression. Am J Respir Cell Mo! Biol 5:371-376, 1991 14. Cassin S, Dawes GS, Ross BB: Pulmonary blood flow and vascular resistance in immature foetal lambs. J Physiol 171:80-89, 1964 15. Cassin S, Kristova V, Davis T, et al: Tone-dependent responses to endothelin in the isolated perfused fetal sheep pulmonary circulation in situ. J Appl Physiol 70:12281234, 1991 16. Cassin S, Stenmark K, Gause G, et al: Leukotrienes and prostaglandins in fetal lung liquid. J Appl Physiol 68:2214-2222, 1990 17. Cassin S, Winikor I, Tod M, et al: Effects of prostacyclin on the fetal pulmonary circulation. Pediatr Pharmacol 1:197-207, 1981 18. Chapados RA, Steinhorn R, Kamm KE, et al: Increased pulmonary artery myosin heavy chain expression and decreased force generation occur in persistent pulmonary hypertension. Pediatr Res 37:389A, 1995 19. Chatfield BA, McMurtry IF, Hall SL, et al: Hemodynamic effects of endothelin-1 on ovine fetal pulmonary circulation. Am J Physiol 26l:Rl82-R187, 1991 20. Clozel M, Clyman R, Soifer S, et al: Thromboxane is not responsible for the high pulmonary vascular resistance in fetal lambs. Pediatr Res 19:1254-1257, 1985 21. Coffin J, Poole T: Embryonic vascular development: Immunohistochemical identification of the origin and subsequent morphogenesis of the major vessel primordia in quail embryos. Development 102:735-748, 1988
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22. Colebatch H, Dawes G, Goodwin J, et al: The nervous control of the circulation in the foetal and newly expanded lungs of the lamb. J Physiol 178:544-562, 1965 23. Cook C, Weiser MCM, Schwartz PE, et al: Developmentally timed expression of an embryonic growth phenotype in vascular smooth muscle cells. Circ Res 74:189-196, 1994 24. Cornfield DN, Chatfield BA, McQueston JA, et al: Effects of birth-related stimuli on L-arginine-dependent pulmonary vasodilation in the ovine fetus. Am J Physiol 262 (Heart Circ Physiol 31):H1474-H1481, 1992 25. Davidson D: Pulmonary hemodynamics at birth: Effect of acute cyclooxygenase inhibition in lambs. J Appl Physiol 64:1676-1682, 1988 26. Dawes GS, Mott JC, Rennick BB: Some effects of adrenaline, noradrenaline and acetylcholine on the fetal circulation of the lamb. J Physiol 134:139, 1956 27. De Ruiter MC, Poelman RE, van Iperen L, et al: The early development of the tunica media in the vascular system of rat embryos. Anat Embryol 181:341-349, 1990 28. Dempsey EC, Badesch DB, Dobyns EL, et al: Enhanced growth capacity of neonatal pulmonary artery smooth muscle cells in vitro: Dependence on cell size, time from birth, insulin-like growth factor I, and auto-activation of protein kinase C. J Cell Physiol 160:469-481, 1994 29. Fineman JR, Wong J, Morin IFC, et al: Chronic nitric oxide inhibition in utero produces persistent pulmonary hypertension in newborn lambs. J Clin Invest 93:26752683, 1994 30. Fisher SA, Ikebe M: Developmental and tissue distribution of expression of nonmuscle and smooth muscle isoforms of myosin light chain kinase. Biochem Biophys Res Commun 217:696-703, 1995 31. Fu YM, Spirito P, Yu ZX, et al: Acidic fibroblast growth factor in the developing rat embryo. J Cell Biol 114:1261-1273, 1991 32. Gao Y, Zhou H, Raj JU: Endothelium-derived nitric oxide plays a larger role in pulmonary veins than in arteries of newborn lambs. Circ Res 76:559-565, 1995 33. Gao Y, Zhou H, Raj JU: Heterogeneity in endothelium-derived nitric oxide mediated relaxation along pulmonary vascular tree in newborn lambs. Am J Respir Crit Care Med 151:A516, 1995 34. Gause GE, Baker R, Cassin S: Specificity of FPL 57231 for leukotriene D 4 receptors in fetal pulmonary circulation. Am J Physiol 254:H120-125, 1988 35. Glukhova MA, Frid MG, Koteliansky VE: Developmental changes in the expression of contractile and cytoskeletal proteins in human aortic smooth muscle. J Biol Chem 265:13042-13046, 1990 36. Gordon JB, Hortop J, Hakim TS: Developmental effects of hypoxia and indomethacin on distribution of vascular resistances in lamb lungs. Pediatr Res 23:580-584, 1989 37. Gordon JB, Tod ML, Wetzel RC, et al: Age-dependent effects of indomethacin on hypoxic vasoconstriction in neonatal lamb lungs. Pediatr Res 23:580-584, 1988 38. Green RS, Leffler CW: Hypoxia stimulates prostacyclin synthesis by neonatal lungs. Pediatr Res 18:832-836, 1984 39. Halbower AC, Tuder RM, Franklin WA, et al: Maturation-related changes in endothelial nitric oxide synthase immunolocalization in developing ovine lung. Am J Physiol 267:L585-L591, 1994 40. Hall S, Haworth SG: Conducting pulmonary arteries: Structural adaptation to extrauterine life. Cardiovasc Res 21:208, 1986 41. Han RN, Mawdsley C, Souza P, et al: Platelet-derived growth factors and growthrelated genes in rat lung: III. Immunolocalization during fetal development. Pediatr Res 31:323-329, 1992 42. Han VKM, D'Ercole AJ, Lung PK: Cellular localization of somatomedin (insulin-like growth factor) messenger RNA in the human fetus. Science 230:193-197, 1987 43. Heine UI, Munoz EF, Flanders KC, et al: Role of transforming growth factor-[3 in the development of the mouse embryo. J Cell Biol 105:2861-2876, 1987 44. Heine UI, Munoz EF, Flanders KC, et al: Colocalization of TGF-beta 1 and collagen I and III, fibronectin and glycosaminoglycans during lung branching morphogenesis. Development 109:29-36, 1990
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45. Heymam1 MA, Rudolph AM, Nies AS, et al: Bradykinin production associated with oxygenation of the fetal lamb. Circ Res 25:521-534, 1969 46. Hislop A, Reid L: Intrapulmonary arterial development during fetal life: Branching pattern and structure. J Anat 113:35, 1975 47. Hislop A, Reid LM: Formation of the pulmonary vasculature. [n Hodson WA (eds): Development of the Lung. New York, Marcel Dekker, 1977, pp 37-86 48. Ibe BO, Raj JU: Developmental differences in production of lipoxygenase metabolites by ovine lungs. Exp Lung Res 21:385-405, 1995 49. Iwamoto J, Morin FC III: Nitric oxide inhibition varies with hemoglobin saturation. J Appl Physiol 75:2332-2336, 1993 50. Jia L, Bonaventura C, Bonaventura J, et al: S-nitrosohaemoglobin: A dynamic activity of blood involved in vascular control. Nature 380:221-226, 1996 51. Jones OW, Abman SH: Systemic and pulmonary hemodynamic effects of big endothelin-1 and phosphoramidon in the ovine fetus. Am J Physiol 266:R929-935, 1994 52. Kinsella JP, Ivy DD, Abman SH: Ontogeny of NO activity and response to inhaled NO in the developing ovine pulmonary circulation. Am J Physiol 267:Hl955-H1961, 1994 53. Klagsbrun M: The fibroblast growth factor family: Structural and biological properties. Progress in Growth Factor Research 1:207-235, 1989 54. Konduri GG, Gervasio CT, Theodorou AA: Role of adenosine triphosphate and adenosine in oxygen-induced pulmonary vasodilation in fetal lambs. Pediatr Res 33:533-539, 1993 55. Konduri GG, Theodorou AA, Mukhopadhyay A, et al: Adenosine triphosphate and adenosine increase the pulmonary blood flow to postnatal levels in fetal lambs. Pediatr Res 31:451-457, 1992 56. Kostyk SK, Kourembanas S, Wheeler EL, et al: Basic fibroblast growth factor increases nitric oxide synthase production in bovine endothelial cells. Am J Physiol 269:Hl583H1589, 1995 57. Kourembanas S, McQuillan LP, Leung GK, et al: Nitric oxide regulates the expression of vasoconstrictors and growth factors by vascular endothelium under both normoxia and hypoxia. J Clin Invest 92:99-104, 1993 58. Leffler CW, Hessler JR: Pulmonary and systemic vascular effects of exogenous prostaglandin 12 in fetal lambs. Eur J Pharmacol 54:37-42, 1979 59. Leffler CW, Hessler JR, Green RS: Mechanism of stimulation of pulmonary prostacyclin synthesis at birth. Prostaglandins 28:877-887, 1984 60. Leffler CW, Hessler JR, Green RS: The onset of breathing at birth stimulates pulmonary vascular prostacyclin synthesis. Pediatr Res 18:938-942, 1984 61. Leffler CW, Tyler TC, Cassin S: Effect of indomethacin on pulmonary vascular response to ventilation of fetal goats. Am J Physiol 234:H346-51, 1978 62. Leffler CW, Tyler TL, Cassin S: Responses of pulmonary and systemic circulations of perinatal goats to prostaglandin F200 Can J Physiol Pharmacol 57:167-173, 1979 63. Levy M, Tulloh RMR, Komai H, et al: Maturation of the contractile response and its endothelial modulation in newborn porcine intrapulmonary arteries. Pediatr Res 38:25-29, 1995 64. Lewis AB, Heymmm MA, Rudolph AM: Gestational changes in pulmonary vascular responses in fetal lambs in utero. Circ Res 39:536-541, 1976 65. Liu LM, Nicoll CS: Evidence for a role of basic fibroblast growth factor in rat embryonic growth and differentiation. Endocrinology 123:2027-2031, 1988 66. Liu SF, Hislop AA, Haworth SG, et al: Developmental changes in endothelium dependent pulmonary vasodilatation in pigs. Br J Pharmacol 106:324-330, 1992 67. Lock J, Olley P, Coceani F: Direct pulmonary vascular response to prostaglandins in the conscious newborn lamb. Am J Physiol 238:H631-638, 1980 68. Loesch A, Burnstock G: Ultrastructural localization of nitric oxide synthase and endothelin in coronary and pulmonary arteries of newborn rats. Cell Tissue Res 279:475-483, 1995 69. Majack RA: Extinction of autonomous growth potential in embryonic: Adult vascular smooth muscle cell heterokaryons. J Clin Invest 95:464-468, 1995 70. Malek A, Izumo S: Mechanism of endothelial cell shape change and cytoskeletal remodeling in response to fluid shear stress. J Cell Science 109:713-726, 1996
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71. McQuillan LP, Leung GK, Marsden PA, et al: Hypoxia inhibits expression of eNOS via transcriptional and post-transcriptional mechanisms. Am J Physiol 267:H19211927, 1994 72. Mills AN, Haworth SG: Pattern of connective tissue development in swine pulmonary vasculature by immunolocalization. J Pathol 153:171-176, 1987 73. Morin F III: Hyperventilation, alkalosis, prostaglandins, and the pulmonary circulation of the newborn. J Appl Physiol 61:2088-2094, 1986 74. Morin FC III: Persistent pulmonary hypertension of the newborn. In Emmanouilides EC, Allen HD, Riemenschneider TA, Gugesell HP (eds): Heart Disease in Infants, Children, and Adolescents. Baltimore, Williams & Wilkins, 1995, pp 599-614 75. Morin FC III, Egan EA: Pulmonary hemodynamics in fetal lambs during development at normal and increased oxygen tension. J Appl Physiol 73:213-218, 1992 76. Morin FC III, Egan EA, Ferguson W, et al: Development of pulmonary vascular response to oxygen. Am J Physiol 254:H542-546, 1988 77. Morin FC III, Egan EA, Lundgren CEG, et al: Prostacyclin does not change during an oxygen induced increase in pulmonary blood flow in the fetal lamb. Prostaglandins, Leukotrienes & Essential Fatty Acids 32:139-144, 1988 78. Morin FC III, Egan EA, Norfleet WT: Indomethacin does not diminish the pulmonary vascular response of the fetus to increased oxygen tension. Pediatr Res 24:696-700, 1988 79. Nishio E, Fukushima K, Shiozaki M, et al: Nitric oxide donor SNAP induces apoptosis in smooth muscle cells through cGMP-independent mechanism. Biochem Biophys Res Commun 221:163-168, 1996 80. North AJ, Brannon TS, Wells LB, et al: Hypoxia stimulates prostacyclin synthesis in newborn pulmonary artery endothelium by increasing cyclooxygenase-1 protein. Circ Res 75:33-40, 1994 81. North AJ, Lau KS, Brannon TS, et al: Oxygen upregulates nitric oxide synthase gene expression in ovine fetal pulmonary artery endothelial cells. Am J Physiol 270:L643-L649, 1996 82. North AJ, Star RA, Brannon TS, et al: Nitric oxide synthase type I and type III gene expression are developmentally regulated in rat lung. Am J Physiol 266:L635-L641, 1994 83. Owens G, Thompson M: Developmental changes in isoactin expression in rat aortic smooth muscle cells in vivo. J Biol Chem 261:13373-13380, 1986 84. Peters K, Werner S, Liao X, et al: Targeted expression of a dominant negative FGF receptor blocks branching morphogenesis and epithelial differentiation of the mouse lung. EMBO J 13:3296-3301, 1994 85. Poole T, Coffin J: Vasculogenesis and angiogenesis: Two distinct morphogenetic mechanisms establish embryonic vascular pattern. J Exp Zoo! 251:224-231, 1989 86. Redding GJ, McMurtry I, Reeves JT: Effects of meclofenamate on pulmonary vascular resistance correlate with postnatal age in young piglets. Pediatr Res 18:579-583, 1984 87. Reid D, Thornburg K: Pulmonary pressure-flow relationships in the fetal lamb during in utero ventilation. J Appl Physiol 69:1630-1636, 1990 88. Risau W, Sariola H, Zerwes H-G, et al: Vasculogenesis and angiogenesis in embryonic-stem-cell-derived embryoid bodies. Development 102:471-478, 1988 89. Ross R, Raines EW, Bowen-Pope DF: The biology of platelet-derived growth factor. Cell 46:155-169, 1986 90. Rudolph AM, Heymann MA: Circulatory changes during growth in the fetal lamb. Circ Res 26:289-299, 1970 91. Sakurai T, Yanagisawa M, Takuwa Y, et al: Cloning of a cDNA encoding a nonisopeptide-selective subtype of the endothelin receptor. Nature 348:732-735, 1990 92. Sanchez LS, Filippov G, Zapol WM, et al: cGMP-binding, cGMP-specific phosphodiesterase gene expression is regulated during lung development. Pediatr Res 37:348A, 1995 93. Schmidt HHHW, Lohmann SM, Walter U: The nitric oxide and cGMP signal transduction system: Regulation and mechanism of action. Biochim Biophys Acta 1178:153175, 1993
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94. Shaul PW, Wells LB: Oxygen modulates nitric oxide production selectively in fetal pulmonary endothelial cells. Am J Respir Cell Mol Biol 11:432-438, 1994 95. Shaul PW, Campbell WB, Farrar MA, et al: Oxygen modulates prostacyclin synthesis in ovine fetal pulmonary arteries by an effect on cyclooxygenase. J Clin Invest 90:2147-2155, 1992 96. Shaul PW, Farrar MA, Magness RR: Oxygen modulation of pulmonary arterial prostacyclin synthesis is developmentally regulated. Am J Physiol 265:H621-H628, 1993 97. Shaul PW, Farrar MA, Zellers TM: Oxygen modulates endothelium-derived relaxing factor production in fetal pulmonary arteries. Am J Physiol 262 (Heart Circ Physiol 3l):H355-H364, 1992 98. Shaul PW, Muntz KH, DeBeltz D, et al: Ontogeny of the adenylate cyclase system in the pulmonary vascular smooth muscle of the fetal lamb. J Cardiovasc Pharmacol 17:125-133, 1991 99. Soifer S, Loitz R, Roman C, et al: Leukotriene end organ antagonists increase pulmonary blood flow in fetal lambs. Am J Physiol 249:H570-576, 1985 100. Soifer SJ, Schreiber MD, Heymann MA: Leukotriene antagonists attenuate thromboxane-inducible pulmonary hypertension. Pediatr Res 26:83-87, 1989 101. Steinhorn RH, Millard SL, Morin FC III: Persistent pulmonary hypertension of the newborn: Role of nitric oxide and endothelin in pathophysiology and treatment. Clin Perinatol 22:405-428, 1995 102. Steinhorn RH, Morin FC III, Gugino SF, et al: Developmental differences in endothelium-dependent responses in isolated ovine pulmonary arteries and veins. Am J Physiol 264:H2162-H2167, 1993 103. Steinhorn RH, Morin FC III, VanWylen DGL, et al: Endothelium-dependent relaxations to adenosine in juvenile rabbit pulmonary arteries and veins. Am J Physiol 266:H2001-H2006, 1994 104. Steinhorn RH, Russell JA, Morin F III: Disruption of cyclic GMP production in pulmonary arteries isolated from fetal lambs with pulmonary hypertension. Am J Physiol 268:Hl483-Hl489, 1995 105. Teitel D, Iwamoto H, Rudolph A: Changes in the pulmonary circulation during birthrelated events. Pediatr Res 27:372-378, 1990 106. Thompson WJ: Cyclic nucleotide phosphodiesterases: Pharmacology, biochemistry and function. Pharmacol Ther 51:13-33, 1991 107. Tiktinsky MH, Cummings JJ, Morin FC III: Acetylcholine increases pulmonary blood flow in intact fetuses via endothelium-dependent vasodilation. Am J Physiol 262 (Heart Circ Physiol 31):406-410, 1992 108. Tiktinsky MH, Morin FC III: Increasing oxygen tension dilates fetal pulmonary circulation via endothelium-derived relaxing factor. Am J Physiol 265:H376-H380, 1993 109. Tod M, Cassin S: Effects of 6-keto-prostaglandin E1 on perinatal pulmonary vascular resistance. Proc Soc Exp Biol Med 166:148-152, 1981 llO. Tod ML, Cassin S: Perinatal pulmonary responses to arachidonic acid during normoxia and hypoxia. J Appl Physiol 57:977-983, 1984 lll. Tod ML, Cassin S: Thromboxane synthase inhibition and perinatal pulmonary response to arachidonic acid. J Appl Physiol 58:710-716, 1985 112. Tod ML, Yoshimura K, Rubin LJ: Indomethacin prevents ventilation-induced decreases in pulmonary vascular resistance of the middle region in fetal lambs. Pediatr Res 29:449-454, 1991 113. Tyler TL, Leffler CW, Cassin S: Circulatory responses of perinatal goats to prostaglandin precursors. Prostaglandins Med 1:213-229, 1978 114. Uematsu M, Ohara Y, Navas JP, et al: Regulation of endothelial cell nitric oxide synthase mRNA expression by shear stress. Am J Physiol 269:C1371-C1378, 1995 ll5. Vane JR, Vanhoutte PM, Botting R: Preface for the proceedings of the Third International Conference on Endothelin. J Cardiovasc Pharmacol 22:ix-x, 1993 116. Velvis H, Krusell J, Roman C, et al: Leukotrienes C 4 , D4 , and E4 in fetal lamb tracheal fluid. J Dev Physiol 14:37-41, 1990 117. Velvis H, Moore PH, Heymann MA: Prostaglandin inhibition prevents the fall in
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pulmonary vascular resistance as a result of rhythmic distension of the lungs in fetal lambs. Pediatr Res 30:62-68, 1991 Wang W, Coceani F: Isolated pulmonary resistance vessels from fetal lambs: Contractile behaviors and responses to indomethacin and endothelin-1. Circ Res 71 :320-330, 1992 Wang Y, Coceani F: EDRF in pulmonary resistance vessels from fetal lamb: Stimulation by oxygen and bradykinin. Am J Physiol 266 (Heart Circ Physiol 35):H936H943, 1994 Wang Y, Coe Y, Toyoda 0, et al: Involvement of endothelin-1 in hypoxic pulmonary vasoconstriction in the lamb. J Physiol 482:421-434, 1995 Weibel ER: Design of airways and blood vessels considered as branching trees. In Crystal RG, West JB (eds): The Lung: Scientific Foundations. New York, Raven Press, 1991, p 711 Winters JW, Wong J, VanDyke D, et al: Endothelin receptor blockade does not alter the increase in pulmonary blood flow due to oxygen ventilation in fetal lambs. Pediatr Res 40:152-157, 1996 Wong J, Vanderford PA, Winters JW, et al: Endothelin-1 does not mediate acute hypoxic pulmonary vasoconstriction in the intact newborn lamb. J Cardiovasc Pharmacol 22:S262-266, 1993 Xue C, Reynolds PR, Johns RA: Developmental expression of NOS isoforms in fetal rat lung: Implications for transitional circulation and pulmonary angiogenesis. Am J Physiol 270:L88-L100, 1996 Yanagisawa M, Inoue A, Ishikawa T, et al: Primary structure, synthesis, and biological activity of rat endothelin, an endothelium-derived vasoconstrictor peptide. Proc Natl Acad Sci USA 85:6964-6967, 1988 Zellers TM, Vanhoutte PM: Endothelium-dependent relaxations of piglet pulmonary arteries augment with maturation. Pediatr Res 30:176-180, 1991 Zetter B: Endothelial heterogeneity: Influence of vessel size, organ localization, and species specificity on the properties of cultured endothelial cells. In Ryan US (eds): Endothelial Cells. Boca Raton, FL, CRC Press, 1988, p 63 Ziegler JW, Ivy DD, Fox JJ, et al: Dipyridamole, a cGMP phosphodiesterase inhibitor, causes pulmonary vasodilation in the ovine fetus. Am J Physiol 269:H473-H479, 1995
Address reprint requests to Robin H. Steinhorn, MD Division of Neonatology Children's Hospital of Buffalo 219 Bryant Street Buffalo, NY 14222 e-mail: [email protected]
0095-5108/96 $0.00
+ .20
THE NORMAL PULMONARY VASCULAR TRANSITION BIRTH Robert C. Dukarm, MD, Robin H. Steinhorn, MD, and Frederick C. Morin IIt MD
It is critical to establish the foundation of the multiple processes involved in the normal pulmonary vascular transition at birth to understand its pathogenesis and pathophysiology in the infant with congenital diaphragmatic hernia. In most neonates, the normal pulmonary vascular transition occurs quickly in the delivery room. To understand this "transition/' we must realize that underlying it is the process of fetal lung development that begins several weeks after conception and is not complete until several days to weeks after birth. We will therefore review the embryogenesis of the pulmonary vasculature, including angiogenesis and vasculogenesis, as well as the possible role that growth factors, growth inhibitors, and mechanical forces have in the normal development of the pulmonary vasculature. We will also review the vasoactive substances that modulate vascular tone in the fetus. Finally, we will look at the stimuli that initiate the transition at birth and the agents that may mediate it. We have reviewed some of this material in more detail elsewhere. 74• 101
NORMAL PULMONARY VASCULAR DEVELOPMENT
Structural
There is a close association of pulmonary arterial and airway development. At week 4 of human development, an endodermal pair of lung From the Division of Neonatology (RCD, RHS, FCM), Departments of Pediatrics (RCD, RHS, FCM) and Physiology (FCM), State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, New York
CLINICS IN PERINATOLOGY VOLUME 23 •NUMBER 4 •DECEMBER 1996
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buds arise from the esophagus, surrounded by mesenchyme containing a vascular network. These vessels accompany developing airways as they differentiate into arteries, and go on to join the larger pulmonary arteries that originate from the sixth branchial arch. 4 ' 121 As gestation progresses, synchronization of airway and vessel branching occurs, 46, 47 indicating they potentially respond to common mediators or exchange messenger molecules. The veins arise separately from the loose mesenchyme of the lung septa and subsequently connect to the developing left atrium. Angiogenesis and vasculogenesis are two morphogenetic processes that contribute to the development of the pulmonary vasculature. Vasculogenesis begins with differentiation and segregation of angioblasts from mesodermal tissues. These endothelial cell precursors migrate, adhere, and form vascular channels that become arteries, veins, or lymphatics depending on local factors. Angioblasts contribute to the expression of smooth muscle phenotype in the surrounding mesenchyme, or they recruit existing smooth muscle cells (SMC) to the forming vessel. Angiogenesis, the budding or sprouting of new vessels from preexisting vessels or vascular channels, then occurs. Within the buds are distinct zones of migration, proliferation, differentiation, and basement membrane formation that result in the formation of new vessels. 21 ' 85, 88 Therefore, there are probably distinct embryonic origins for endothelial and vascular smooth muscle cells in the proximal and distal vasculature, which could account for their subsequent differences in functional behavior. 33, 127 Proliferation of endothelial cells, SMCs, and fibroblasts is necessary for continued pulmonary vascular growth. Although exact mechanisms controlling vascular growth are not known, the production of local growth factors is likely involved. Basic and acidic fibroblast growth factors (FGF), which are present in the major vessels of embryonic rats, 31 are potent angiogenic factors. 53 Blockade of the FGF receptor in a transgenic mouse model results in ablation of branching morphogenesis of the lung,84 and antibodies to the basic FGF retard vascular development.65 Basic FGF increases endothelial mRNA and protein synthesis of nitric oxide synthase, and NO production, suggesting that part of its effects may be mediated through N0. 56 Transforming growth factor-beta (TGF-[3) has also been shown to be coupled with pronounced angiogenic activity43 and to increase the production of collagens I and III and proteoglycans by lung fibroblasts. 44 Platelet-derived growth factor (PDGF) may be an important factor in vascular development and cell differentiation. Both PDGF isoforms and receptors are expressed in the developing lung,13, 41 and PDGF is mitogenic for vascular SMC and fibroblasts. 89 Insulin-like growth factor (IGF) mRNA expression has been demonstrated by in situ hybridization to be present in pulmonary arteries of the human fetus. 42 Both IGF I and II stimulate SMC and fibroblast proliferation, and they increase elastin and collagen production in neonatal pulmonary vascular walls. 8 Neonatal pulmonary artery SMC may be more sensitive to IGF I than are those from adults. 28 Although growth factors are likely important, vascular growth in the fetus also occurs
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independently of growth factors. For instance, vascular SMC isolated from fetal rat aorta replicate by mechanisms independent of growth factors, which is distinct from the adult phenotype requiring exogenous mitogens. 23 • 69 As development progresses, the embryonic endothelial channels acquire a smooth muscle layer 27 and, therefore, the ability to generate vascular tone and regulate blood flow. Structurally, pulmonary arterial SMC change during development. 40• 72 Actin and myosin, the two major contractile proteins, exist as structural isoforms whose expression is developmentally regulated. 83 As development of the vascular wall progresses, a transition occurs from the [3-nonmuscle to the smooth muscle specific a-actin isoform. 35 At least four heavy chain myosin isoforms have been identified: two smooth muscle (SM) isoforms and two nonmuscle (NM) or synthetic isoforms. 30 The expression of all four appears to be developmentally regulated in the chick embryo. 30 Increased expression of the synthetic isoforms may explain the decreased responsiveness to constrictors observed in pulmonary arteries isolated from immature sheep and piglets as compared with adult animals. 18• 63 Up to 70% of the mass of the wall of large pulmonary arteries is composed of elastin and collagen produced by smooth muscle cells. Elastin provides the vessel with distensibility, and collagen provides it with rigidity. Many of the growth factors mentioned previously are likely involved in the regulation of elastin and collagen synthesis. The majority of elastin production takes place during fetal life and essentially none occurs after the first decade. Collagen has several chemical types, whose expression varies with age. Types V and III are most abundant in the pulmonary arteries isolated from neonatal pigs. 72 During normal postnatal development expression of the high tensile strength type I collagen increases. These changes may partially explain the relatively high compliance of the neonatal circulation and the subsequent adapations that occur in the postnatal period. Mediators of High Fetal Pulmonary Vascular Tone Much of our understanding of the regulation of the fetal circulation comes from experiments done in the fetal lamb. From 85 to 145 days of gestation (term= 146 days), the number of small blood vessels increases 40-fold, whereas the wet weight of the lung increases fourfold. 64 Therefore, the number of small blood vessels per unit of lung increases 10fold. Despite this increase in the number of vessels, fetal pulmonary circulation is characterized by high arterial pressure and high vascular resistance, and pulmonary blood flow does not increase. 75 Right ventricular output instead bypasses the lungs through the foramen ovale and ductus arteriosis, and it provides blood flow to the organ of gas exchange, the placenta. In the fetus, only 5% to 10% of the combined cardiac output flows to the lungs, whereas 50% flows to the placenta. 75 • 90 Because the fetal pulmonary vascular bed responds readily to vasodila-
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Table 1. PROPOSED MEDIATORS OF PULMONARY VASCULAR TONE IN FETAL AND TRANSITIONAL CIRCULATION Vasoconstrictors (Maintain High Fetal PVR)
Vasodilators (Decrease PVR During Transition)
Norepinephrine cx-Adrenergic stimulation Hypoxia Endothelin Thromboxane Leukotrienes Platelet activating factor PGF2"
PG!,, PGD 2, PGE 2 Nitric oxide cGMP Oxygen Adenosine ATP Bradykinin
PVR = pulmonary vascular resistance; PG = prostaglandin; cGMP = cyclic guanosine monophosphate; ATP = adenosine triphosphate.
tors, 107 this high-resistance, low-flow state is probably maintained in part by vasoconstriction. Hypoxic pulmonary vasoconstriction, sympathetic tone, norepinephrine, arachidonic acid metabolites, and endothelin are potential mechanisms and mediators. to explain the high fetal vascular tone (Table 1). Although electrical stimulation and norepinephrine increase pulmonary vascular resistance in the fetal lamb,10• 14• 22 neither sympathectomy nor alpha-adrenergic blockade decreases the resistance. 10• 22 Therefore, sympathetic tone does not appear to be responsible for the high pulmonary vascular resistance of the fetus. Arachidonic acid constricts the pulmonary circulation of the fetus and newborn. no, 113 Its cyclooxygenase products, prostaglandin F2"' and thromboxane A 2 are synthesized by the fetal lung16 and are vasoconstrictors in the fetal and newborn lung. 62• 67 Blocking prostaglandin or thromboxane synthesis, however, does not decrease vascular resistance, 20• rn. n 7 suggesting that these metabolites may not be responsible for the high vascular resistance in the fetus. Leukotrienes are metabolites of arachidonic acid via the lipoxygenase pathway. Leukotriene D4 is a potent vasoconstrictor in the fetal and newborn lamb, an effect that may be mediated by thromboxane release. 100 Leukotriene receptor antagonists/ synthesis inhibitors increase fetal pulmonary blood flow manyfold, 34• 99 although this may be due to nonspecific vasodilating effects. 34 Leukotriene concentrations in the fetal lung liquid are less than concentrations that would be expected to cause vasoconstriction, 16• n 6 and production is significantly higher in adult sheep as compared with newborn and fetal sheep. 48 Therefore, additional studies are needed in this area to determine if leukotrienes are important in maintaining high fetal vascular tone. Vasoconstriction in response to low oxygen tension may contribute to high pulmonary vascular resistance in the fetus. Hypoxic pulmonary vasoconstriction develops over the period of gestation when the crosssectional area of the vascular bed is increasing rapidly. Decreasing
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oxygen tension in the fetus at 103 days of gestation does not increase pulmonary vascular resistance, but in the 132-to-138 day fetus it doubles the resistance. 64 Conversely, increasing oxygen tension before 100 days of gestation does not decrease pulmonary vascular resistance, but by 135 days it decreases resistance markedly and increases pulmonary blood flow to normal newborn levels.75 • 76 Although the mechanism by which low fetal oxygen tension regulates pulmonary vascular tone is not known, it may be in part through regulation of activity and gene expression of nitric oxide synthase71 • 81• 94 and/ or endothelin. 57 In addition, acute decreases in oxygen tension decrease prostacyclin synthesis in pulmonary arteries isolated from fetal lambs. 96 Endothelin is an endothelium-derived peptide with potent vasoconstrictor properties, and it therefore could cause high vascular tone. Three isoforms of this 21-amino acid peptide have been characterized, termed endothelin-1, endothelin-2, and endothelin-3. Endothelin is generated from a 203-amino acid peptide called preproendothelin, which is cleaved to a 92-amino acid form, big endothelin-1. Endothelin-converting enzyme cleaves big endothelin-1 to endothelin-1, which is 100 times more potent.1 25 Endothelin binds to specific ET A and the ET 8 receptors that have been cloned and characterized. 5 • 91 ET-1 binds with high affinity to the ETA receptor that is predominantly expressed in vascular smooth muscle and mediates vasoconstriction. The ET 8 receptor binds all three isopeptides with equal affinity. It is more widely distributed in cell types of various tissues, including endothelial cells. Endothelial ET 8 receptors mediate vasodilation, but recent studies propose that this receptor also mediates vasoconstriction in certain tissues, including the rabbit pulmonary artery. 115 The role of endothelin in determining fetal and transitional pulmonary vascular resistance is unclear. Intrapulmonary infusions of ET-1 transiently dilate the pulmonary vascular bed of the intact fetal lamb. 15• 19 In contrast, intrapulmonary infusions of big endothelin-1 constrict this same vascular bed,51 an effect that is reversed by phosphoramidon, an inhibitor of the endothelin-converting enzyme. Endothelin-1 constricts pulmonary arteries and veins isolated from fetal lambs. 118• 12° Furthermore, endothelin-1 infusions increase pulmonary arterial pressure in newborn lambs 123 and in fetal lambs ventilated with 100% oxygen. 15 These data indicate that the effects of exogenous endothelin are complex and depend on the site, developmental age, and tone of the vascular bed. Plasma concentrations of endothelin-1 are highest in immediate newborn piglets, and they decrease steadily in the subsequent 10 days of life. 63 Low oxygen tension, possibly by decreasing nitric oxide production, induces the expression and secretion of endothelin-1 in cultured human endothelial cells. 57 Endothelin receptor blockade, however, does not block the increase in pulmonary arterial pressure in the intact newborn lamb exposed to hypoxia, 123 and conversely it does not block the increase in pulmonary blood flow following oxygen ventilation of the fetal lamb .122
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THE TRANSITION AT BIRTH
At birth, a dramatic decrease in pulmonary vascular resistance allows half of the combined ventricular output to be redirected from the placenta to the organ of gas exchange in the newborn, the lung. This decrease in pulmonary vascular resistance leads to an 8- to 10-fold increase in pulmonary blood flow. The increase in pulmonary blood flow increases the pressure in the left atrium, which closes the one-way flap valve of the foramen ovale. Systemic vascular resistance increases at birth, at least in part due to removal of the low vascular resistance bed of the placenta. The largest immediate drop in pulmonary vascular resistance occurs at birth; however, this resistance continues to drop over the first several months of life until it reaches the low level normally found in the adult circulation. As pulmonary vascular resistance falls to less than systemic, blood flow through the patent ductus arteriosus reverses. Over the first several hours of life the ductus arteriosus functionally closes, largely in response to the increased oxygen tension of the newborn. The ductus arteriosus may not anatomically close for several months. It is critical that all of these events occur within the first several hours of life for the normal postnatal pattern of circulation to be established. The stimuli that seem to be most important in decreasing pulmonary vascular resistance are (1) ventilation of the lungs with a gas, (2) lowering carbon dioxide tension, and (3) raising oxygen tension in the lungs. Each of these stimuli by itself will decrease pulmonary vascular resistance and increase pulmonary blood flow. 87, 105 The largest effects are seen when the three occur simultaneously. Intrauterine ventilation of the fetal lamb, without changing the arterial tension of carbon dioxide or oxygen, increases pulmonary blood flow to approximately two thirds of that observed following birth. 87, 105 To study the effect of raising oxygen tension without ventilating the lung, chronically instrumented fetal lambs were studied while the ewe breathed oxygen in a hyperbaric chamber at three atmospheres absolute. 6, 45 During hyperbaric oxygenation, fetal pulmonary vascular resistance decreases and pulmonary blood flow increases to levels comparable to after birth. 75, 76, 78 Agents Mediating Transition
Prostaglandins have been proposed as important mediators of the transition at birth. Indomethacin and meclofenomate, both inhibitors of prostaglandin synthesis, blunt the decrease in pulmonary vascular resistance noted when the fetal lung is ventilated with a gas. 61 , m, 117 Whereas PGI 2 and PGD2 are fetal pulmonary vasodilators, PGI2 seems to be the prostaglandin involved in the transition. It can be quantified by measuring its stable hydrolysis metabolite 6-keto-PGF]c,. Prostacyclin and its metabolites dilate the fetal pulmonary vascular bed. 17, 5 s, 62, 109 PGI 2 synthesis in ovine PA endothelium and vascular smooth muscle in-
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creases markedly during late fetal and early newborn life. 12• 96 This increase is due to a rise in cyclooxygenase activity related to enhanced expression of cyclooxygenase-1. 12 Following birth, there is a switch from net clearance to net production of PGI 2 by the lungs. 59• 60 The effect of oxygen tension on prostaglandin production in the fetal and newborn lung is complex. Increasing oxygen tension increases PGI2 synthesis in pulmonary arteries isolated from fetal lambs 95 ; however, indomethacin does not block the increase in fetal pulmonary blood flow and decrease in pulmonary vascular resistance produced in hyperbaric chamber,78 and fetal plasma levels of the metabolite 6-keto-PGF 1a are not changed during hyperbaric oxygenation. 77 In postnatal lambs, acute hypoxia directly stimulates cyclooxygenase gene expression and PGI 2 and PGE 2 synthesis in endothelial cells and isolated lungs. 38• so. 96 Prostacyclin synthesis by the lung during hypoxia may be greater in the immediate newborn period than later in life, and it may thus provide a protective mechanism against hypoxic vasoconstriction. 36 • 37 The relative role of prostacyclin during normal transition is not certain. PGl 2 production declines within hours after birth, and the initial net production by the lungs may revert to net clearance within days after birth. 60• 73 Furthermore, the increase in pulmonary vascular resistance caused by meclofenomate sharply declines after birth, and by 12 days of age it has no hemodynamic effects. 86 Indomethacin only modestly increases pulmonary artery pressure in term lambs at birth. 25 Its effect on the transition to gas exchange by the lungs at birth is variable. 25 • 112 Activity of adenylate cyclase, the effector mechanism producing dilation to prostacyclin, decreases as the fetus approaches term. 97 This may explain why the role of prostaglandins seems to be more important in the preterm fetus. 61 The role of endothelial derived nitric oxide during fetal lung development and transition has been under intensive investigation. Nitric oxide (NO) is produced from the terminal nitrogen of arginine by nitric oxide synthase (Fig. 1). All three of the known nitric oxide synthase (NOS) isoforms are present and developmentally regulated in the fetal rat lung. 68 • 82• 124 Immunostaining for the endothelial constitutive (type III) NOS isoform in the fetal lamb lung peaks during midgestation and decreases postnatally. 39 Recent studies suggesting that NO may induce apoptotic cell death in vascular SMC 79 further support a role for NO in lung vascular development. Developmental and locational differences also exist in the functional activity of NOS. NOS activity can be demonstrated as early as 117 to 120 days' gestation in the fetal lamb. 52 Basal and stimulated release of NO from pulmonary arteries from the near term fetus appear diminished, however, when compared with the amount released postnatally.3· 66 • 102• 126 NOS function may vary with location in the vasculature. Pulmonary veins from fetal and newborn lambs release more NO than do pulmonary veins from older lambs. 102 Pulmonary veins are also more responsive to exogenous NO than are pulmonary arteries. 32• 33 • 102• 104
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Oxygen Birth Shear Stress
Acetylcholine Bradykinin
L-NA L-NMMA
""-<±> Receptor
~
Endothelial Cell
NO
r-5Yntha~ Arginine
Citrulline
Vascular Smooth Muscle Cell
NO
<±> +
Soluble guanylate cyclase
GTP Phosphodiesterase
5'GM
Relaxation
Figure 1. The proposed mechanism of synthesis and action of nitric oxide (NO). NO is produced in the endothelium from the terminal guanido nitrogen of L-arginine by NO synthase. NO synthase can be stimulated by pharmacologic agents such as acetylcholine or bradykinin, as well as by birth, shear stress, and oxygen. Endothelial production of NO can be blocked by arginine analogues that have modifications of the guanido nitrogen of the molecule. NO activates soluble guanylate cyclase, increases cGMP concentrations in vascular smooth muscle, and initiates the cascade resulting in smooth muscle relaxation. The magnitude and duration of the effect of cGMP is controlled by its inactivation by specific phosphodiesterases. cGMP = guanosine 3' ,5' -cyclic monophosphate; GMP guanosine 5' monophosphate; GTP = guanosine 5' triphosphate.
Venodilation may play an important role in producing the increased pulmonary blood flow seen normally following birth. Stimulating NO production mimics the transition by dilating the fetal pulmonary vascular bed. The pulmonary vasodilation produced by
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acetylcholine in the fetal lamb 26 can be blocked by the arginine analogues L-NA and L-NMMA and restored by excess L-arginine, indicating that acetylcholine is stimulating endothelial NOS. 2 • 107 Blocking NOS activity with the arginine analogue L-NA immediately prior to delivery of the fetal lamb blunts the increase in pulmonary blood flow and decrease in pulmonary vascular resistance following birth. 2 Furthermore, when LNA is infused into fetal lambs for 10 days prior to birth at doses that do not increase basal pulmonary vascular tone, the decrease in vascular tone and the increase in pulmonary blood flow normally seen at birth are significantly blunted in lambs, and pulmonary arterial pressure remains equal to aortic pressure. 29 Oxygen is probably an important stimulus for endothelial NO production during transition. The increased pulmonary blood flow following hyperbaric oxygenation of the fetal lamb is almost completely blocked by L-NA (Fig. 2). 108 The mechanisms for the increase in NO release related to increased oxygen tension are not clear. Both basal and stimulated release of endothelial NO increase when oxygen tension is acutely increased in pulmonary arteries isolated from late-gestation fetal lambs, 97 • 119 and NO production is attenuated following acute decreases in oxygenation in cultured fetal pulmonary arterial cells. 94 Changes in oxygen tension regulate NOS gene expression in fetal pulmonary arterial cells81 and human endothelial cells. 71 Other mechanisms may exist in
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Figure 2. Effect of hyperbaric oxygen (squares) and the L-arginine derivatives L-NMMA (circles) and L-NA (triangles) on pulmonary blood flow in fetal lambs. L-NMMA was infused following 30 minutes of hyperbaric oxygenation; L-NA was infused 30 minutes prior to hyperbaric oxygenation. Values are means ± SE. * Significantly different from period prior to hyperbaric oxygenation. t Significantly different from control group. (Adapted from Tiktinsky MH, and FC Morin Ill: Increasing oxygen tension dilates fetal pulmonary circulation via endothelium-derived relaxing factor. Am J Physiol 265:376-380, 1993, with permission.)
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vivo. For instance, bradykinin, which stimulates endothelial NO production, increases during hyperbaric oxygenation of fetal sheep 45; however, blockage of the bradykinin receptors responsible for pulmonary vasodilation does not block the response to ventilation with oxygen. 9 Oxygen increases red blood cell adenosine triphosphate (ATP), which is a fetal pulmonary vasodilator and potential stimulus for endothelial NO production. 55, 103 Infusion of purine receptor antagonists blocks the pulmonary vasodilation to oxygen in the fetal lamb. 54 Finally, NO binding to hemoglobin may be altered when it becomes fully saturated after birth.49, so Shear stress increases the synthesis of NO in the fetal pulmonary circulation. 24 In bovine, rabbit, and human aortic endothelial cells, mRNA expression and activity of endothelial constitutive NOS increase following shear stress.7· 114 The regulation of this response is complex and may involve fundamental alterations in regulation of endothelial NO synthase activity.7 During transition, an initial increase in pulmonary blood flow produced by ventilation or increased oxygen tension may increase shear stress, which then increases NO synthesis and further enhances the increase in pulmonary-blood flow. Shear stress may lead to further postnatal adaptation of the pulmonary circulation by increasing expression of 13-actin mRNA and producing cytoskeletal remodeling in endothelial cells. 70 Cyclic guanosine monophosphate (cGMP) mediates the vascular smooth muscle relaxation produced by NO. Infusions of cGMP analogues, or of atrial natriuretic factor, which stimulates cGMP production by particulate guanylate cyclase, produce prolonged dilations of the pulmonary circulation of the fetal lamb. 1 The magnitude and duration of cGMP effect is regulated by specific phosphodiesterase isoforms (PDE). 93, 106 Expression of the cGMP-specific (type V) PDE is developmentally regulated in rat lung, 92 and inhibition of cGMP phosphodiesterases dilates the pulmonary vascular bed of normal fetal lambs.11, 128 These relaxations are blocked with L-NA, suggesting they are due to enhancement of the effect of cGMP generated in response to endogenous NO. The interaction between cyclic adenosine monophosphate (cAMP) and cGMP may be also important in the transition at birth. Both nucleotides compete for clearance by type I (calcium/ calmodulin-stimulated) PDE, and cGMP inhibits the clearance of cAMP by type III PDE. 106
SUMMARY
Although the normal pulmonary vascular transition at birth takes place quickly in the delivery room, it has its basis in the complex structural and biochemical development of the lung. We are only beginning to understand the stimuli that initiate and mediate the transition, as well as their interrelationships. Comprehension of normal structure and function is the foundation that will enable us to understand how
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Address reprint requests to Robin H. Steinhorn, MD Division of Neonatology Children's Hospital of Buffalo 219 Bryant Street Buffalo, NY 14222 e-mail: [email protected]