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Collateral growth: cells arrive at the construction site
PII: S0967-2109(02)00108-4
Cardiovascular Surgery, Vol. 10, No. 6, pp. 570–578, 2002 2002 The International Society for Cardiovascular Surgery. Published by Elsevier Science Ltd. All rights reserved. 0967-2109/02 $22.00
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Collateral growth: cells arrive at the construction site Claudia Heilmann, Friedhelm Beyersdorf and Georg Lutter Division of Cardiovascular Surgery, Department of Surgery, School of Medicine, Albert-LudwigsUniversity Freiburg, Freiburg, Germany Coronary artery disease (CAD) and peripheral artery occlusion disease are the most common diseases in the Western world which are treated by pharmacological and surgical therapies. However, patients in the endstage of the disease are not suitable candidates for bypass surgery. Alternative therapies that boost the endogenous collateralization are required. Two mechanisms are naturally activated after onset of ischemia: 1. angiogenesis, sprouting of capillaries, and 2. arteriogenesis, enlargement of small preexisting arterioles. In the first part of this review, we describe the sequence of events during the development of collateral vessels. The second part focuses on two types of cells which are crucial for the development of collateral circulation, and which migrate to the site of vessel growth via peripheral blood: monocytes/macrophages and endothelial progenitor cells. The role of these cells and the implications for their use in treating ischemic diseases of cardiac and sceletal muscle are discussed. 2002 The International Society for Cardiovascular Surgery. Published by Elsevier Science Ltd. All rights reserved.
Abbreviations HIF-1 Hypoxia-inducible factor-1 FGF-2 Fibroblast growth factor-2 FGF-R1 FGF receptor-1 PDGF Platelet derived growth factor ICAM-1 Intercellular adhesion molecule-1 VEGF Vascular endothelial growth factor VEGF-R1/2 VEGF receptor-1/-2 MC/MP smonocytes/macrophages EPC sendothelial progenitor cells IL-1β Interleukin-1β Egr-1/-3 Early growth response factor-1/-3 MCP-1 Monocyte chemoattractant (or chemotactic) protein-1 GM-CSF Granulocyte monocyte-colony stimulating factor SMC Smooth muscle cell EPC Endothelial progenitor cell.
Correspondence to: G. Lutter. Tel./fax: +49 761 270 2874; e-mail: [email protected]
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Introduction Coronary artery disease (CAD) and peripheral artery occlusion disease are the most common diseases in the Western world. If an angioplasty of the affected arteries is not possible, the therapeutical goal is to bypass the stenosed or occluded vessels. Since the 1950s, various surgical techniques have been developed to restore blood supply to almost all organs using bypass procedures. However, patients in the endstage of ischemic heart or limb diseases cannot undergo bypass surgery or balloon dilatation. Other therapy is necessary. One alternative is to support the endogenous development of collateral vessels occurring naturally after onset of ischemia. However, the development of collateral circulation develops insufficiently in a large number of patients or does not develop at all. An efficient therapy must boost the endogeneous collateralization process. Stenosis or occlusion of arterial vessels triggers two pathophysiological conditions: tissue ischemia and shear stress in the remaining arterioles and arteries. These circumstances initiate a cascade of changes mediated by growth factors, cytokines, CARDIOVASCULAR SURGERY
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chemokines, and ephrins, which are responsible for the patterning of the arterial and veneous system [1]. Ischemia and vessel wall shearing also attract cells circulating in the peripheral blood to the site of vessel growth. Shear stress exerted on vascular endothelial cells initiates immigration and attachment of monocytes and macrophages, whereas ischemia results in remote mobilization of endothelial progenitor cells from bone marrow, which settle in developing capillaries. Two mechanisms of endogeneous collateralization are activated in the ischemic area: First, ischemia triggers sprouting of capillaries. Endothelial cells covering the walls of these new vessels consist of expanded and immigrated endothelial cells of parental vessels or are recruited from endothelial progenitor cells circulating in the peripheral blood. Second, there is a preexisting system of collaterals made up of arterioles. Due to physiological demand, these arterioles can enlarge and achieve a higher transportation capacity. This process depends, at least in part, on the activity of monocytes and macrophages [2]. Depending on their size, arterial vessels account for a much larger share of perfusion than capillaries [3,4]. Therefore, arteriogenesis must be an indispensible part of the process of collateralization. Yet, the relationship of angiogenesis and arteriogenesis for the development of collateral circulation is not completely elucidated [5]. The first part of this review outlines the development of collateral circulation under ischemic conditions for both sceletal and cardiac muscle. The second chapter discusses the relevance of two cell types that approach the ischemic construction site by the residual blood stream: monocytes/macrophages and endothelial progenitor cells. In the last century the cellular and molecular basics for understanding endogeneous vessel growth have been discovered and preliminary data concerning therapeutic angiogenesis have been collected. Therefore, our goal in this century will be to optimize therapeutic arteriogenesis by developing ideal revascularization methods.
Development of collateral vessels Principles of vessel growth There are three ways in which vessel growth occurs (reviewed by Risau [6], Schaper [7], and Carmeliet [8]). 1. Vasculogenesis: During embryonic development, hematopoietic stem cells differentiate in to a primitive vessel network. 2. Angiogenesis: New vessels sprout out of existing ones. This occurs during embryonic development CARDIOVASCULAR SURGERY
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or under certain circumstances in the adult (eg reproduction, wound healing, tumor growth, or ischemia). In adult tissues, pathologic angiogenesis is frequently named neovascularization or, if medically influenced, therapeutic angiogenesis. The first result of this process is the development of capillaries. 3. Arteriogenesis: Preexisting collateral arterioles, that already have a thin muscle layer, transform into arteries by dilatation, proliferation, and consecutive aquisition of the typical arterial structure. There may be an additional mode of neovascularization. Moldovan et al. [9] describe tunnels in the myocardium, which seem to be drilled by monocytes and macrophages (for details see below). Collateral vessel development in ischemic tissue After the onset of ischemia, reorganization occurs on two different levels within the vessel system. It involves the capillary bed [10] as well as the arterioles [2]. Angiogenesis [6] and arteriogenesis occur in parallel. In the following part, we outline the events subsequent to the sudden onset of sublethal ischemia [11–15]. The cited studies examine the temporal course of events on the molecular level and of vessel growth following surgical occlusion of either coronary vessels or the femoral artery. All these models have in common, that they are performed in healthy animals and simulate a sudden onset of ischemia by partial or complete surgical ligation of a vessel (Table 1). Additional data are provided by studies on human samples [16–18], which analyze ischemic myocardial tissue [16,17] or protein serum levels [18]. In their study on arteriogenesis, Scholz et al. [15] describe four phases following the sudden onset of ischemia: initial phase, proliferation phase, synthetic phase, and maturation phase. Despite minor differences in the determined times of certain events as well as an overlap of the phases, this schedule can Table 1 Experimental settings of animal studies Author
Observation period
Species
Site
Lyn et al. [11] Zimmermann et al. [12] Arras et al. [13] Couffinhal et al. [14] Scholz et al. [15]
30 min–7 days 1–7 days
mouse pig
myocardium myocardium
3–21 days 3–35 days
rabbit mouse
hind limb hind limb
2–240
rabbit
hind limb
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be applied to all models dealing with the development of collateral vessels. In the following section, we attempt to integrate the results from the abovementioned studies in one time-table (Figure 1). Initial phase—0–24 hours. Onset of ischemia triggers an increased level of a number of transcription factors. Upregulation of Early growth response factors (Egr-1 and Egr-3) mRNA begins after 30 min and peaks after 3 h and 24 h, respectively [11]. Egr-1 has been called a ‘master switch’ for ischemically induced genes and mediates expression of growth factors such as FGF2, PDGF-A and –B, and VEGF, cytokines like MCP-1 and IL-1β, adhesion molecules like ICAM1 and CD44, and some others. For more detailed information, we refer to Khachigian et al. [19], Silverman et al. [20], and Yan et al. [21]. There is so far only limited knowledge about the function of Egr-3 in the context of ischemia [22–24]. In human acute myocardial ischemia and in evolving infarction or in early infarction, expression of the transcription factor HIF-1 is detected in the nuclei of cardiomyocytes and endothelial cells lining the small vessels [16]. The β-subunit of HIF-1 is expressed constitutionally, whereas the α-subunit is regulated on the level of mRNA transcription and by proteasome-dependent degradation under normoxic conditions [25]. An intact molecule is only present after onset of ischemia. It mediates the transcription and subsequently the expression of VEGF by binding to the hypoxia response element and is therefore considered essential for ischemia-induced angiogenesis [26]. In addition, VEGF expression under hypoxic
conditions is upregulated by stabilization of mRNA [27]. VEGF is a major angiogenesis factor. It mediates proliferation, migration, and survival of vascular endothelial cells [28,29]. VEGF expression is not directly linked to the presence of HIF. In one human study [16] which examines myocardial biopsies, HIF-1 expression matches the expression of VEGF only in part. The authors distinguish between ischemia and infarction using histological results. Early or evolving infarction are diagnosed from the onset of symptoms (⬍24 h or 24–120 h, respectively). Myocardial ischemia started up to 48 h before sampling. HIF-1 immunoreactivity, e.g. protein expression, is observed in cardiomyocytes and in endothelial cells of small vessels in areas of acute ischemia or of infarction, whereas VEGF expression is seen only in endothelial cells and appears only in ischemia and in evolving but not in early infarction. Thus, there is a time-lapse between HIF-1 and VEGF expression during myocardial infarction. VEGF expression is restricted to the angiogenetically active structures, the small vessels. It is possible, that HIF-1 regulates additional genes in cardiomyocytes. Data from this study indicate that HIF-1 and VEGF are possible markers of different phases of ischemia in human myocardium in vivo. Another study analyses VEGF expression using tissue samples obtained during coronary bypass surgery [17]. Ischemic myocardium was taken from the atrial appendage, which had been ligated for that purpose. According to the description of the procedures, ischemia lasted 2.5 to 5 h. The analysis of protein expression shows elevated levels of VEGF.
Figure 1 Time-course of collateral development
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Moreover, an upregulation of the corresponding receptor VEGF-R1, but not of VEGF-R2 or FGF2 and FGF-R1, is observed. Proliferation is preceded by downregulation of the cell cycle inhibitor p18ink4, whose mRNA transcription is significantly reduced 0.5 to 24 h [11]. Mitotic events as evidenced by in-situ hybridization against histone H3 are apparent 12 hs after onset of ischemia [12]. The nuclear protein Ki-67, which marks cell cycle activity stains positive after 24 h [15]. Twelve hours after the onset of ischemia, ICAM1 (Intercellular Adhesion Molecule-1) and VCAM1 (Vascular Adhesion Molecule-1) are expressed in endothelial and some SMC’s of a number of arterioles indicating activation of these cell types [15]. The first monocytes and macrophages assemble in clusters around the growing vessels [15] and infiltrate regions of irreversibly injured myocytes [12]. This inflammatory infiltration develops through an increase in mononuclear cell numbers. An increase in the numbers of capillaries has already been observed 24 h after onset of ischemia [12]. In summary, the initial phase is characterized by activation of transcription factors mediating the expression of growth factors, cytokines, and adhesion molecules, by immigration of MC/MPs, and by the start of proliferation of endothelial cells. Proliferation phase—1–3 days. Mitosis [13] and proliferation activity of endothelial and smooth muscle cells as well as the presence of monocytes and macrophages inside and around expanding collateral arterioles [13,15] reach their maximum after three days. The accumulated monocytes secrete FGF-2 and TNF-α and induce the inflammatory setting necessary for arteriogenesis [13]. Expression of adhesion molecules by endothelial cells already is subsiding. Proliferation is accompanied by upregulated mRNA transcription of MHC-α (0.5 h to three days) and MLC (maximum at 24 h). These molecules are muscular cytoskeleton proteins, which are known to be involved in cardiac development [11]. Many smooth muscle cells exhibit the synthetic phenotype [13] (for review on smooth muscle cell plasticity, see Halayko and Solway [30]). A decrease in rigidity of the surrounding extracellular matrix is required to form tubular structures by endothelial cells [31]. Therefore, the extracellular matrix is digested by matrix-metalloproteases which are secreted by cardiomyocytes, fibroblasts, smooth muscle cells, and monocytes [32–34]. In conclusion, there is a high mitotic rate of endothelial and smooth muscle cells as well as strong activity of monocytes and macrophages during the proliferation phase. CARDIOVASCULAR SURGERY
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Synthetic phase—3–14 days. Ultrastructural characteristics of strong protein synthesis activity are apparent in all cell types involved in vessel growth. Proliferation activity is still very high at the beginning of the synthetic phase. Seven days after onset of ischemia, first recovery of blood flow in the ischemic limb is observed [14]. In human sera, there is a significant VEGF increase 7 and ten days after acute myocardial infarction. Platelets attracted to the infarcted area are thought to be the main source of VEGF production [18]. Accumulation of monocytes is observed one week after vessel occlusion in areas of capillary growth and is therefore associated not only with arteriogenesis but also with angiogenesis [13]. Subsequently, proliferation activity starts to diminish, Monocytes and macrophages slowly begin to degrade. After ten to 14 days, smooth muscle cells gradually return to the contractile phenotype [13]. Maturation phase—from 2 weeks. Proliferation activity decreases further but remains detectable for about six weeks after femoral artery occlusion [15]. All SMC’s finally aquire a contractile phenotype [13]. Capillary number still slowly increases (in one study up to the last examination 35 days after surgery) and can reach four times that of the nonischemic limb [14]. If these reviewed studies are compared, a similar pattern of events emerges for the development of collateral circulation after sudden onset of ischemia. A slightly different picture of the sequence of events is provided by Hershey et al. [35] in a rabbit hind limb model of sudden ischemia. The investigators distinguish between angiogenesis and arteriogenesis by counting capillaries histologically and determining an angiographic score, respectively. In addition, VEGF expression is measured, and hind limb lactate release serves as a metabolic marker of tissue. All parameters are assessed 5, 10, 20, and 40 days after femoral artery removal. The number of capillaries is higher on day 5 and subsequently reverts. The relationship between capillary quantity and time corresponds with intramuscular VEGF expression, which was detectable only on day 5. Onset of arteriogenesis, however, occurs ten days after vessel occlusion and continues to day 40, the last recorded time. These events do not correlate with VEGF expression or hindlimb venous lactate release. The resting blood flow no longer differs from controls by day 10. Significant improvement of reserve blood flow is observed between day 10 and day 20 as assessed after 40 sec of arterial clipping. These data support the hypothesis that arteriogenesis is more important than angiogenesis in functional blood flow [34]. Development of collateral circulation after onset 573
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of sudden sublethal ischemia can be summarized as follows. In the initial phase, expression of transcription factors follows shortly after onset of ischemia. They initiate a range of growth factors. The activation of the transcription factor Hypoxia induced factor-1 (HIF-1) and subsequent expression of Vascular endothelial growth factor are of special importance. The first 24 h are further characterized by onset of endothelial cell proliferation, expression of adhesion molecules, and activation of monocytes and macrophages. A high mitotic activity of endothelial and smooth muscle cells is present during the proliferation phase for 24 h to three days. Monocytes and macrophages provide an appropriate environment by secreting growth factors, cytokines, and metalloproteinases. VEGF expression and accumulation of monocytes and macrophages peak after seven days during the synthetic phase, which ranges from day 3 to 14. Proliferation activity diminishes and first recovery of blood flow is observed. There is still limited proliferation in the following maturation phase, while vessel number and structure reach their final state. The studies discussed above include experiments in healthy animals as well as data from human patients. Despite the comparability of the results, the course of events described above might be vary due to physiological factors such as grade of atherosclerosis, age [36], hypercholesterolaemia [37], or diabetes [38]. In addition, all in vivo experiments are hampered by the fact, that every diagnostic or therapeutical procedure itself adds parameters to the process of vessel growth such as degree of intrusiveness of the operation or immunological reactions.
Role of monocytes/macrophages and endothelial progenitor cells As discussed above, onset of ischemia and subsequent development of collateral vessels involves a number of different cell types. Among these cells, there are two types of cells, that are not recruited from the local tissue, but immigrate from remote territory and arrive at the site of ischemia by peripheral blood: monocytes/macrophages and endothelial progenitor cells. Both have distinct functions in the development of collateral circulation and mediate a range of direct or indirect effects, which are discussed in the following chapter (Figure 2). Monocytes and macrophages (MC/MP’s) Monocytes and macrophages play an indispensable but not finally elucidated role in collateral vessel development [2]. Monocyte Chemotactic Protein-1 (MCP-1), also known as Monocyte Chemoattrac574
Figure 2 Spatial course of collateral development
tant Protein-1, is the most potent stimulator for monocyte migration [39]. The expression of MCP-1 is regulated by different mechanisms. Firstly, its expression is controlled by the growth factors VEGF and FGF-2 [40,41]. Secondly, after onset of ischemia, increased shear force and cyclic strain in the remaining intact vessels induce an increased expression of MCP-1 by the affected vascular endothelial cells [42,43]. It is synthesized by a variety of cells, among them vascular endothelial cells, smooth muscle cellss, cardiomyocytes, and interstitial fibroblasts [44] as well as by bone marrow [45] and peripheral blood mononuclear leukocytes [46]. In addition, it mediates the dedifferentiation of smooth muscle cells from contractile to synthetic phenotype [47]. Based on these observations, Ito and coworkers [48] and Hoefer et al. [49] examine the effect of MCP-1 on collateral artery growth. They employ a rabbit hind limb ischemia model with occlusion of the femoral artery and apply MCP-1 locally via an osmotic minipump. This treatment results in an increased density of collateral arteries in the thigh area and of capillaries in the lower leg. The peripheral conductance, however, was significantly increased compared to the buffer control only one week, but not three weeks after ligation [49]. It is possible that monocytes and macrophages play an even more direct role in the development of collateral vessels than providing the appropriate environment [9]. Transgenic mice expressing MCP1 selectively in the heart were examined for macrophage activity. This model resulted in an ischemic cardiac disease with occlusion of coronary vessels and small arterioles by cellular and thrombotic material. The authors describe a network of tunnels crossing the myocardial interstitium which was absent in CARDIOVASCULAR SURGERY
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wild-type mice. They suggest that these channels were drilled by monocytes and macrophages (MC/MPs). The tubular structures contain no endothelium and stain positive for metalloelastase, a broad-spectrum metalloproteinase specific for MC/MPs. The staining intensity is stronger in the subendocardial myocardium suggesting a higher activity of MC/MPs in the ischemic area. In the tunnels, MC/MPs and occasionally erythrocytes are found. The authors postulate that the tunnels could become colonized by endothelial cells or their precursors, respectively, based on staining against a hematopoietic stem cell marker, Thy-2, and cellular morphology. To test their idea, they transplanted MCP-1 overexpressing hearts into mice whose epithelial cells were transgenically marked by β-galactosidase and found infiltration of MCP-1 hearts by these cells. So far, it is not clear whether these tunnels help improve perfusion and myocardial function of the ischemic hearts. Although, further studies are required to examine the effects on the number of vessels as well as on hemodynamics and may prove the authors’ hypothesis. In conclusion, stimulating and directing the activity of monocytes and macrophages by specific cytokines could be a useful tool to improve the development of collateral circulation. Endothelial progenitor cells (EPCs) EPCs are descendents of pluripotent mesenchymal hemangiopoietic stem cells. In adults, they originate in the bone marrow and circulate in the peripheral blood. They are committed to differentiation but still have the CD34 antigen. EPCs have been shown to migrate to the hot spots of physiological as well as pathological angiogenesis [50]. As a result of intense research in the field of bone marrow transplantation, there is generally extensive knowledge about progenitor cells. In contrast, the role of endothelial progenitor cells was clarified only lately. Whereby, there were three significant problems: Firstly, only a very small number of circulating cells are EPCs. In 1998 their existence was first proven [51]. Secondly, a specific combination of surface markers which would have enabled the identification of these cells was unknown. Thirdly, a cultivation method was needed, that would allow preservation and expansion of the incompletely differentiated EPCs. In 2000, circulating EPCs were shown to be characterized by combined expression of CD34, AC133, and VEGF receptor 2 (VEGFR-2) [52,53]. CD34 has been considered the ‘classical’ hematopoietic stem cell marker for a number of years but might be upregulated only in response to proliferation signals and therefore represent a marker of activated stem cells [54,55]. AC133, first described in 1997 [56,57], is a five transmembrane domain antiCARDIOVASCULAR SURGERY
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gen of about 120 kDa and is expressed on a subset of CD34+ cells and on certain epithelial cells where it migrates to the apical region [58]. Its physiological function remains to be elucidated. VEGFR-2 is found on hematopoietic stem cells [59] and on pluripotent vascular progenitor cells, that develop into endothelial cells, pericytes, and smooth muscle cells [60]. In peripheral blood mobilized with G-CSF, only about 2% of the already rare CD34+ cells additionally express AC133 and VEGFR-2 [52]. Other groups successfully employed a doublestaining method to identify EPCs, which utilizes endocytosis of acetylated low density lipoproteins (acLDL) and binding of Ulex europaeus agglutinin [61] or the combined assessment of acLDL incorporation, nitric oxide release, expression of von Willebrand factor, and lectin binding [62]. EPCs are mobilized from bone marrow by different mechanisms. Stimulation by G-CSF and GMCSF as typical in transplantation medicine triggers an unspecific increase in cell numbers in peripheral blood [63]. A more specific increase of EPCs is obtained by VEGF application [64–67]. However, it is not known whether this is directly mediated by the VEGF receptor-2 or is an indirect effect. Endogenous mobilization of EPC’s is observed in response to ischemia of both limbs and heart [68,69]. By implementing bone marrow transplantation, the migrating progenitor cells can be proven to originate in the bone marrow. Bone marrow or endothelial progenitor cells, respectively, are taken from an animal with a different genetic background, e.g. expressing a reporter gene, derived from the opposite gender or even from a different species. They are transplanted into the recepient and can be tracked by reporter gene expression or by assessment of the appropriate genetic difference. Further, it is possible to label cells prior to injection with an intracellular fluorescent dye [70] or to transfect them with a reporter gene. This procedure enables the targeted expression of proteins which promote or inhibit vessel growth [71]. Cultures of unselected bone marrow cells express VEGF and MCP-1, which subsequently induce endothelial cell proliferation [45]. Transplantation of bone marrow cells into ischemic hind limb muscle results in angiogenesis and improved muscle function [72]. Similiar results are obtained in a porcine [45] and rat ischemic myocardium model [70]. The latter authors showed an increased capillary count one week after therapy which already decreases one week later. This event is interpreted as downregulation of supernumerous vessels (compare Hershey et al. [35]). A significant increase in proinflammatory cytokines like IL-1β and cytokine-induced neutrophil chemoattractant during the first three days is considered to be an expression of the transplanted 575
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bone marrow cells. Injection of bone marrow cells into the borders of infarcted myocardium promotes development of both myocytes and vascular structures [73]. EPCs circulating in peripheral blood selectively settle into angiogenetic foci and have a therapeutical effect in an ischemic environment as demonstrated in an myocardial model in rats [74] and in a hindlimb model in mice [61]. Human ECPs which are retrieved from human blood and expanded in vitro, are injected intracardially or intravenously. The EPCs find their way to the site of ischemia and accumulate in foci of angiogenesis. Success of the treatment is confirmed by enhanced neovascularization and increased limb perfusion or lesser ventricular scarring compared to controls. No effect is found with already differentiated human microvascular endothelial cells (HMVEC) or with the supernatant of the EPC culture, respectively. Therefore, only the progenitor cells themselves and not their secreted products are responsible for the neovascularization effect [61,74]. Thus, approaches for mobilization or exogeneous application of native or manipulated endothelial progenitor cells may be able to promote the building of collateral vessels.
Conclusions There are a number of highly convincing approaches, both from the theoretical and from the practical point of view, to enhance collateral circulation development in ischemic tissues. Onset of ischemia triggers two reactions: Firstly, ischemia itself induces angiogenesis, that is sprouting of new capillaries. Endothelial progenitor cells from peripheral blood migrate to this site and differentiate to new endothelium. Secondly, arteriogenesis is initiated by increased perfusion in the remaining vessels. The shear stress leads to activation of monocytes and macrophages and subsequent transformation of preexisting collaterals to larger arterioles and arteries. The time course of development of collaterals is comparable in all models of sudden onset of ischemia. The idea, that only larger vessels maintain perfusion is highly convincing and supported by in vivo experiments [35,48,49]. Therefore, only arteriogenesis could functionally increase blood supply in ischemic areas. However, therapies which enhance angiogenesis are also able to improve cardiac function [74] and limb blood flow [61,62]. So far there is no resolution in the controversy as to how beneficial capillary and artery growth are and how great a role they play in collateral circulation. Validation of the successful development of collaterals due to therapy can be obtained by different approaches. Firstly, to the patient, only the improve576
ment of quality of life is important. Secondly, the physician is also interested in clinical parameters, for instance, blood flow or stress tolerance. Thirdly, direct imaging and quantification of the newly developed collaterals enables an analysis of local effects. Considering the impact of ischemic diseases of the heart and limbs on the individual as well as on the society, a treatment that is able to boost the collateralization process, is highly desirable.
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68. Asahara, T., Murohara, T., Sullivan, A. et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science, 1997, 275, 964–967. 69. Shintani, S., Murohara, T., Ikeda, H. et al. Mobilization of endothelial progenitor cells in patients with acute myocardial infarction. Circulation, 2001, 103, 2776–2779. 70. Kobayashi, T., Hamano, K., Li, T. S. et al. Enhancement of angiogenesis by the implantation of self bone marrow cells in a rat ischemic heart model. J Surg Res, 2000, 89, 189–195. 71. Gomez-Navarro, J., Contreras, J. L., Arafat, W. et al. Genetically modified CD34+ cells as cellular vehicles for gene delivery into areas of angiogenesis in a rhesus model. Gene Ther, 2000, 7, 43–52. 72. Ikenaga, S., Hamano, K., Nishida, M. et al. Autologous bone marrow implantation induced angiogenesis and improved deteriorated exercise capacity in a rat ischemic hindlimb model. J Surg Res, 2001, 96, 277–283. 73. Orlic, D., Kajstura, J., Chimenti, S. et al. Bone marrow cells regenerate infarcted myocardium. Nature, 2001, 410, 701–705. 74. Kawamoto, A., Gwon, H. C., Iwaguro, H. et al. Therapeutic potential of ex vivo expanded endothelial progenitor cells for myocardial ischemia. Circulation, 2001, 103, 634–637. Paper accepted 15 May 2002
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Cardiovascular Surgery, Vol. 10, No. 6, pp. 570–578, 2002 2002 The International Society for Cardiovascular Surgery. Published by Elsevier Science Ltd. All rights reserved. 0967-2109/02 $22.00
www.elsevier.com/locate/cardiosur
Collateral growth: cells arrive at the construction site Claudia Heilmann, Friedhelm Beyersdorf and Georg Lutter Division of Cardiovascular Surgery, Department of Surgery, School of Medicine, Albert-LudwigsUniversity Freiburg, Freiburg, Germany Coronary artery disease (CAD) and peripheral artery occlusion disease are the most common diseases in the Western world which are treated by pharmacological and surgical therapies. However, patients in the endstage of the disease are not suitable candidates for bypass surgery. Alternative therapies that boost the endogenous collateralization are required. Two mechanisms are naturally activated after onset of ischemia: 1. angiogenesis, sprouting of capillaries, and 2. arteriogenesis, enlargement of small preexisting arterioles. In the first part of this review, we describe the sequence of events during the development of collateral vessels. The second part focuses on two types of cells which are crucial for the development of collateral circulation, and which migrate to the site of vessel growth via peripheral blood: monocytes/macrophages and endothelial progenitor cells. The role of these cells and the implications for their use in treating ischemic diseases of cardiac and sceletal muscle are discussed. 2002 The International Society for Cardiovascular Surgery. Published by Elsevier Science Ltd. All rights reserved.
Abbreviations HIF-1 Hypoxia-inducible factor-1 FGF-2 Fibroblast growth factor-2 FGF-R1 FGF receptor-1 PDGF Platelet derived growth factor ICAM-1 Intercellular adhesion molecule-1 VEGF Vascular endothelial growth factor VEGF-R1/2 VEGF receptor-1/-2 MC/MP smonocytes/macrophages EPC sendothelial progenitor cells IL-1β Interleukin-1β Egr-1/-3 Early growth response factor-1/-3 MCP-1 Monocyte chemoattractant (or chemotactic) protein-1 GM-CSF Granulocyte monocyte-colony stimulating factor SMC Smooth muscle cell EPC Endothelial progenitor cell.
Correspondence to: G. Lutter. Tel./fax: +49 761 270 2874; e-mail: [email protected]
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Introduction Coronary artery disease (CAD) and peripheral artery occlusion disease are the most common diseases in the Western world. If an angioplasty of the affected arteries is not possible, the therapeutical goal is to bypass the stenosed or occluded vessels. Since the 1950s, various surgical techniques have been developed to restore blood supply to almost all organs using bypass procedures. However, patients in the endstage of ischemic heart or limb diseases cannot undergo bypass surgery or balloon dilatation. Other therapy is necessary. One alternative is to support the endogenous development of collateral vessels occurring naturally after onset of ischemia. However, the development of collateral circulation develops insufficiently in a large number of patients or does not develop at all. An efficient therapy must boost the endogeneous collateralization process. Stenosis or occlusion of arterial vessels triggers two pathophysiological conditions: tissue ischemia and shear stress in the remaining arterioles and arteries. These circumstances initiate a cascade of changes mediated by growth factors, cytokines, CARDIOVASCULAR SURGERY
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chemokines, and ephrins, which are responsible for the patterning of the arterial and veneous system [1]. Ischemia and vessel wall shearing also attract cells circulating in the peripheral blood to the site of vessel growth. Shear stress exerted on vascular endothelial cells initiates immigration and attachment of monocytes and macrophages, whereas ischemia results in remote mobilization of endothelial progenitor cells from bone marrow, which settle in developing capillaries. Two mechanisms of endogeneous collateralization are activated in the ischemic area: First, ischemia triggers sprouting of capillaries. Endothelial cells covering the walls of these new vessels consist of expanded and immigrated endothelial cells of parental vessels or are recruited from endothelial progenitor cells circulating in the peripheral blood. Second, there is a preexisting system of collaterals made up of arterioles. Due to physiological demand, these arterioles can enlarge and achieve a higher transportation capacity. This process depends, at least in part, on the activity of monocytes and macrophages [2]. Depending on their size, arterial vessels account for a much larger share of perfusion than capillaries [3,4]. Therefore, arteriogenesis must be an indispensible part of the process of collateralization. Yet, the relationship of angiogenesis and arteriogenesis for the development of collateral circulation is not completely elucidated [5]. The first part of this review outlines the development of collateral circulation under ischemic conditions for both sceletal and cardiac muscle. The second chapter discusses the relevance of two cell types that approach the ischemic construction site by the residual blood stream: monocytes/macrophages and endothelial progenitor cells. In the last century the cellular and molecular basics for understanding endogeneous vessel growth have been discovered and preliminary data concerning therapeutic angiogenesis have been collected. Therefore, our goal in this century will be to optimize therapeutic arteriogenesis by developing ideal revascularization methods.
Development of collateral vessels Principles of vessel growth There are three ways in which vessel growth occurs (reviewed by Risau [6], Schaper [7], and Carmeliet [8]). 1. Vasculogenesis: During embryonic development, hematopoietic stem cells differentiate in to a primitive vessel network. 2. Angiogenesis: New vessels sprout out of existing ones. This occurs during embryonic development CARDIOVASCULAR SURGERY
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or under certain circumstances in the adult (eg reproduction, wound healing, tumor growth, or ischemia). In adult tissues, pathologic angiogenesis is frequently named neovascularization or, if medically influenced, therapeutic angiogenesis. The first result of this process is the development of capillaries. 3. Arteriogenesis: Preexisting collateral arterioles, that already have a thin muscle layer, transform into arteries by dilatation, proliferation, and consecutive aquisition of the typical arterial structure. There may be an additional mode of neovascularization. Moldovan et al. [9] describe tunnels in the myocardium, which seem to be drilled by monocytes and macrophages (for details see below). Collateral vessel development in ischemic tissue After the onset of ischemia, reorganization occurs on two different levels within the vessel system. It involves the capillary bed [10] as well as the arterioles [2]. Angiogenesis [6] and arteriogenesis occur in parallel. In the following part, we outline the events subsequent to the sudden onset of sublethal ischemia [11–15]. The cited studies examine the temporal course of events on the molecular level and of vessel growth following surgical occlusion of either coronary vessels or the femoral artery. All these models have in common, that they are performed in healthy animals and simulate a sudden onset of ischemia by partial or complete surgical ligation of a vessel (Table 1). Additional data are provided by studies on human samples [16–18], which analyze ischemic myocardial tissue [16,17] or protein serum levels [18]. In their study on arteriogenesis, Scholz et al. [15] describe four phases following the sudden onset of ischemia: initial phase, proliferation phase, synthetic phase, and maturation phase. Despite minor differences in the determined times of certain events as well as an overlap of the phases, this schedule can Table 1 Experimental settings of animal studies Author
Observation period
Species
Site
Lyn et al. [11] Zimmermann et al. [12] Arras et al. [13] Couffinhal et al. [14] Scholz et al. [15]
30 min–7 days 1–7 days
mouse pig
myocardium myocardium
3–21 days 3–35 days
rabbit mouse
hind limb hind limb
2–240
rabbit
hind limb
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be applied to all models dealing with the development of collateral vessels. In the following section, we attempt to integrate the results from the abovementioned studies in one time-table (Figure 1). Initial phase—0–24 hours. Onset of ischemia triggers an increased level of a number of transcription factors. Upregulation of Early growth response factors (Egr-1 and Egr-3) mRNA begins after 30 min and peaks after 3 h and 24 h, respectively [11]. Egr-1 has been called a ‘master switch’ for ischemically induced genes and mediates expression of growth factors such as FGF2, PDGF-A and –B, and VEGF, cytokines like MCP-1 and IL-1β, adhesion molecules like ICAM1 and CD44, and some others. For more detailed information, we refer to Khachigian et al. [19], Silverman et al. [20], and Yan et al. [21]. There is so far only limited knowledge about the function of Egr-3 in the context of ischemia [22–24]. In human acute myocardial ischemia and in evolving infarction or in early infarction, expression of the transcription factor HIF-1 is detected in the nuclei of cardiomyocytes and endothelial cells lining the small vessels [16]. The β-subunit of HIF-1 is expressed constitutionally, whereas the α-subunit is regulated on the level of mRNA transcription and by proteasome-dependent degradation under normoxic conditions [25]. An intact molecule is only present after onset of ischemia. It mediates the transcription and subsequently the expression of VEGF by binding to the hypoxia response element and is therefore considered essential for ischemia-induced angiogenesis [26]. In addition, VEGF expression under hypoxic
conditions is upregulated by stabilization of mRNA [27]. VEGF is a major angiogenesis factor. It mediates proliferation, migration, and survival of vascular endothelial cells [28,29]. VEGF expression is not directly linked to the presence of HIF. In one human study [16] which examines myocardial biopsies, HIF-1 expression matches the expression of VEGF only in part. The authors distinguish between ischemia and infarction using histological results. Early or evolving infarction are diagnosed from the onset of symptoms (⬍24 h or 24–120 h, respectively). Myocardial ischemia started up to 48 h before sampling. HIF-1 immunoreactivity, e.g. protein expression, is observed in cardiomyocytes and in endothelial cells of small vessels in areas of acute ischemia or of infarction, whereas VEGF expression is seen only in endothelial cells and appears only in ischemia and in evolving but not in early infarction. Thus, there is a time-lapse between HIF-1 and VEGF expression during myocardial infarction. VEGF expression is restricted to the angiogenetically active structures, the small vessels. It is possible, that HIF-1 regulates additional genes in cardiomyocytes. Data from this study indicate that HIF-1 and VEGF are possible markers of different phases of ischemia in human myocardium in vivo. Another study analyses VEGF expression using tissue samples obtained during coronary bypass surgery [17]. Ischemic myocardium was taken from the atrial appendage, which had been ligated for that purpose. According to the description of the procedures, ischemia lasted 2.5 to 5 h. The analysis of protein expression shows elevated levels of VEGF.
Figure 1 Time-course of collateral development
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Moreover, an upregulation of the corresponding receptor VEGF-R1, but not of VEGF-R2 or FGF2 and FGF-R1, is observed. Proliferation is preceded by downregulation of the cell cycle inhibitor p18ink4, whose mRNA transcription is significantly reduced 0.5 to 24 h [11]. Mitotic events as evidenced by in-situ hybridization against histone H3 are apparent 12 hs after onset of ischemia [12]. The nuclear protein Ki-67, which marks cell cycle activity stains positive after 24 h [15]. Twelve hours after the onset of ischemia, ICAM1 (Intercellular Adhesion Molecule-1) and VCAM1 (Vascular Adhesion Molecule-1) are expressed in endothelial and some SMC’s of a number of arterioles indicating activation of these cell types [15]. The first monocytes and macrophages assemble in clusters around the growing vessels [15] and infiltrate regions of irreversibly injured myocytes [12]. This inflammatory infiltration develops through an increase in mononuclear cell numbers. An increase in the numbers of capillaries has already been observed 24 h after onset of ischemia [12]. In summary, the initial phase is characterized by activation of transcription factors mediating the expression of growth factors, cytokines, and adhesion molecules, by immigration of MC/MPs, and by the start of proliferation of endothelial cells. Proliferation phase—1–3 days. Mitosis [13] and proliferation activity of endothelial and smooth muscle cells as well as the presence of monocytes and macrophages inside and around expanding collateral arterioles [13,15] reach their maximum after three days. The accumulated monocytes secrete FGF-2 and TNF-α and induce the inflammatory setting necessary for arteriogenesis [13]. Expression of adhesion molecules by endothelial cells already is subsiding. Proliferation is accompanied by upregulated mRNA transcription of MHC-α (0.5 h to three days) and MLC (maximum at 24 h). These molecules are muscular cytoskeleton proteins, which are known to be involved in cardiac development [11]. Many smooth muscle cells exhibit the synthetic phenotype [13] (for review on smooth muscle cell plasticity, see Halayko and Solway [30]). A decrease in rigidity of the surrounding extracellular matrix is required to form tubular structures by endothelial cells [31]. Therefore, the extracellular matrix is digested by matrix-metalloproteases which are secreted by cardiomyocytes, fibroblasts, smooth muscle cells, and monocytes [32–34]. In conclusion, there is a high mitotic rate of endothelial and smooth muscle cells as well as strong activity of monocytes and macrophages during the proliferation phase. CARDIOVASCULAR SURGERY
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Synthetic phase—3–14 days. Ultrastructural characteristics of strong protein synthesis activity are apparent in all cell types involved in vessel growth. Proliferation activity is still very high at the beginning of the synthetic phase. Seven days after onset of ischemia, first recovery of blood flow in the ischemic limb is observed [14]. In human sera, there is a significant VEGF increase 7 and ten days after acute myocardial infarction. Platelets attracted to the infarcted area are thought to be the main source of VEGF production [18]. Accumulation of monocytes is observed one week after vessel occlusion in areas of capillary growth and is therefore associated not only with arteriogenesis but also with angiogenesis [13]. Subsequently, proliferation activity starts to diminish, Monocytes and macrophages slowly begin to degrade. After ten to 14 days, smooth muscle cells gradually return to the contractile phenotype [13]. Maturation phase—from 2 weeks. Proliferation activity decreases further but remains detectable for about six weeks after femoral artery occlusion [15]. All SMC’s finally aquire a contractile phenotype [13]. Capillary number still slowly increases (in one study up to the last examination 35 days after surgery) and can reach four times that of the nonischemic limb [14]. If these reviewed studies are compared, a similar pattern of events emerges for the development of collateral circulation after sudden onset of ischemia. A slightly different picture of the sequence of events is provided by Hershey et al. [35] in a rabbit hind limb model of sudden ischemia. The investigators distinguish between angiogenesis and arteriogenesis by counting capillaries histologically and determining an angiographic score, respectively. In addition, VEGF expression is measured, and hind limb lactate release serves as a metabolic marker of tissue. All parameters are assessed 5, 10, 20, and 40 days after femoral artery removal. The number of capillaries is higher on day 5 and subsequently reverts. The relationship between capillary quantity and time corresponds with intramuscular VEGF expression, which was detectable only on day 5. Onset of arteriogenesis, however, occurs ten days after vessel occlusion and continues to day 40, the last recorded time. These events do not correlate with VEGF expression or hindlimb venous lactate release. The resting blood flow no longer differs from controls by day 10. Significant improvement of reserve blood flow is observed between day 10 and day 20 as assessed after 40 sec of arterial clipping. These data support the hypothesis that arteriogenesis is more important than angiogenesis in functional blood flow [34]. Development of collateral circulation after onset 573
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of sudden sublethal ischemia can be summarized as follows. In the initial phase, expression of transcription factors follows shortly after onset of ischemia. They initiate a range of growth factors. The activation of the transcription factor Hypoxia induced factor-1 (HIF-1) and subsequent expression of Vascular endothelial growth factor are of special importance. The first 24 h are further characterized by onset of endothelial cell proliferation, expression of adhesion molecules, and activation of monocytes and macrophages. A high mitotic activity of endothelial and smooth muscle cells is present during the proliferation phase for 24 h to three days. Monocytes and macrophages provide an appropriate environment by secreting growth factors, cytokines, and metalloproteinases. VEGF expression and accumulation of monocytes and macrophages peak after seven days during the synthetic phase, which ranges from day 3 to 14. Proliferation activity diminishes and first recovery of blood flow is observed. There is still limited proliferation in the following maturation phase, while vessel number and structure reach their final state. The studies discussed above include experiments in healthy animals as well as data from human patients. Despite the comparability of the results, the course of events described above might be vary due to physiological factors such as grade of atherosclerosis, age [36], hypercholesterolaemia [37], or diabetes [38]. In addition, all in vivo experiments are hampered by the fact, that every diagnostic or therapeutical procedure itself adds parameters to the process of vessel growth such as degree of intrusiveness of the operation or immunological reactions.
Role of monocytes/macrophages and endothelial progenitor cells As discussed above, onset of ischemia and subsequent development of collateral vessels involves a number of different cell types. Among these cells, there are two types of cells, that are not recruited from the local tissue, but immigrate from remote territory and arrive at the site of ischemia by peripheral blood: monocytes/macrophages and endothelial progenitor cells. Both have distinct functions in the development of collateral circulation and mediate a range of direct or indirect effects, which are discussed in the following chapter (Figure 2). Monocytes and macrophages (MC/MP’s) Monocytes and macrophages play an indispensable but not finally elucidated role in collateral vessel development [2]. Monocyte Chemotactic Protein-1 (MCP-1), also known as Monocyte Chemoattrac574
Figure 2 Spatial course of collateral development
tant Protein-1, is the most potent stimulator for monocyte migration [39]. The expression of MCP-1 is regulated by different mechanisms. Firstly, its expression is controlled by the growth factors VEGF and FGF-2 [40,41]. Secondly, after onset of ischemia, increased shear force and cyclic strain in the remaining intact vessels induce an increased expression of MCP-1 by the affected vascular endothelial cells [42,43]. It is synthesized by a variety of cells, among them vascular endothelial cells, smooth muscle cellss, cardiomyocytes, and interstitial fibroblasts [44] as well as by bone marrow [45] and peripheral blood mononuclear leukocytes [46]. In addition, it mediates the dedifferentiation of smooth muscle cells from contractile to synthetic phenotype [47]. Based on these observations, Ito and coworkers [48] and Hoefer et al. [49] examine the effect of MCP-1 on collateral artery growth. They employ a rabbit hind limb ischemia model with occlusion of the femoral artery and apply MCP-1 locally via an osmotic minipump. This treatment results in an increased density of collateral arteries in the thigh area and of capillaries in the lower leg. The peripheral conductance, however, was significantly increased compared to the buffer control only one week, but not three weeks after ligation [49]. It is possible that monocytes and macrophages play an even more direct role in the development of collateral vessels than providing the appropriate environment [9]. Transgenic mice expressing MCP1 selectively in the heart were examined for macrophage activity. This model resulted in an ischemic cardiac disease with occlusion of coronary vessels and small arterioles by cellular and thrombotic material. The authors describe a network of tunnels crossing the myocardial interstitium which was absent in CARDIOVASCULAR SURGERY
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wild-type mice. They suggest that these channels were drilled by monocytes and macrophages (MC/MPs). The tubular structures contain no endothelium and stain positive for metalloelastase, a broad-spectrum metalloproteinase specific for MC/MPs. The staining intensity is stronger in the subendocardial myocardium suggesting a higher activity of MC/MPs in the ischemic area. In the tunnels, MC/MPs and occasionally erythrocytes are found. The authors postulate that the tunnels could become colonized by endothelial cells or their precursors, respectively, based on staining against a hematopoietic stem cell marker, Thy-2, and cellular morphology. To test their idea, they transplanted MCP-1 overexpressing hearts into mice whose epithelial cells were transgenically marked by β-galactosidase and found infiltration of MCP-1 hearts by these cells. So far, it is not clear whether these tunnels help improve perfusion and myocardial function of the ischemic hearts. Although, further studies are required to examine the effects on the number of vessels as well as on hemodynamics and may prove the authors’ hypothesis. In conclusion, stimulating and directing the activity of monocytes and macrophages by specific cytokines could be a useful tool to improve the development of collateral circulation. Endothelial progenitor cells (EPCs) EPCs are descendents of pluripotent mesenchymal hemangiopoietic stem cells. In adults, they originate in the bone marrow and circulate in the peripheral blood. They are committed to differentiation but still have the CD34 antigen. EPCs have been shown to migrate to the hot spots of physiological as well as pathological angiogenesis [50]. As a result of intense research in the field of bone marrow transplantation, there is generally extensive knowledge about progenitor cells. In contrast, the role of endothelial progenitor cells was clarified only lately. Whereby, there were three significant problems: Firstly, only a very small number of circulating cells are EPCs. In 1998 their existence was first proven [51]. Secondly, a specific combination of surface markers which would have enabled the identification of these cells was unknown. Thirdly, a cultivation method was needed, that would allow preservation and expansion of the incompletely differentiated EPCs. In 2000, circulating EPCs were shown to be characterized by combined expression of CD34, AC133, and VEGF receptor 2 (VEGFR-2) [52,53]. CD34 has been considered the ‘classical’ hematopoietic stem cell marker for a number of years but might be upregulated only in response to proliferation signals and therefore represent a marker of activated stem cells [54,55]. AC133, first described in 1997 [56,57], is a five transmembrane domain antiCARDIOVASCULAR SURGERY
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gen of about 120 kDa and is expressed on a subset of CD34+ cells and on certain epithelial cells where it migrates to the apical region [58]. Its physiological function remains to be elucidated. VEGFR-2 is found on hematopoietic stem cells [59] and on pluripotent vascular progenitor cells, that develop into endothelial cells, pericytes, and smooth muscle cells [60]. In peripheral blood mobilized with G-CSF, only about 2% of the already rare CD34+ cells additionally express AC133 and VEGFR-2 [52]. Other groups successfully employed a doublestaining method to identify EPCs, which utilizes endocytosis of acetylated low density lipoproteins (acLDL) and binding of Ulex europaeus agglutinin [61] or the combined assessment of acLDL incorporation, nitric oxide release, expression of von Willebrand factor, and lectin binding [62]. EPCs are mobilized from bone marrow by different mechanisms. Stimulation by G-CSF and GMCSF as typical in transplantation medicine triggers an unspecific increase in cell numbers in peripheral blood [63]. A more specific increase of EPCs is obtained by VEGF application [64–67]. However, it is not known whether this is directly mediated by the VEGF receptor-2 or is an indirect effect. Endogenous mobilization of EPC’s is observed in response to ischemia of both limbs and heart [68,69]. By implementing bone marrow transplantation, the migrating progenitor cells can be proven to originate in the bone marrow. Bone marrow or endothelial progenitor cells, respectively, are taken from an animal with a different genetic background, e.g. expressing a reporter gene, derived from the opposite gender or even from a different species. They are transplanted into the recepient and can be tracked by reporter gene expression or by assessment of the appropriate genetic difference. Further, it is possible to label cells prior to injection with an intracellular fluorescent dye [70] or to transfect them with a reporter gene. This procedure enables the targeted expression of proteins which promote or inhibit vessel growth [71]. Cultures of unselected bone marrow cells express VEGF and MCP-1, which subsequently induce endothelial cell proliferation [45]. Transplantation of bone marrow cells into ischemic hind limb muscle results in angiogenesis and improved muscle function [72]. Similiar results are obtained in a porcine [45] and rat ischemic myocardium model [70]. The latter authors showed an increased capillary count one week after therapy which already decreases one week later. This event is interpreted as downregulation of supernumerous vessels (compare Hershey et al. [35]). A significant increase in proinflammatory cytokines like IL-1β and cytokine-induced neutrophil chemoattractant during the first three days is considered to be an expression of the transplanted 575
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bone marrow cells. Injection of bone marrow cells into the borders of infarcted myocardium promotes development of both myocytes and vascular structures [73]. EPCs circulating in peripheral blood selectively settle into angiogenetic foci and have a therapeutical effect in an ischemic environment as demonstrated in an myocardial model in rats [74] and in a hindlimb model in mice [61]. Human ECPs which are retrieved from human blood and expanded in vitro, are injected intracardially or intravenously. The EPCs find their way to the site of ischemia and accumulate in foci of angiogenesis. Success of the treatment is confirmed by enhanced neovascularization and increased limb perfusion or lesser ventricular scarring compared to controls. No effect is found with already differentiated human microvascular endothelial cells (HMVEC) or with the supernatant of the EPC culture, respectively. Therefore, only the progenitor cells themselves and not their secreted products are responsible for the neovascularization effect [61,74]. Thus, approaches for mobilization or exogeneous application of native or manipulated endothelial progenitor cells may be able to promote the building of collateral vessels.
Conclusions There are a number of highly convincing approaches, both from the theoretical and from the practical point of view, to enhance collateral circulation development in ischemic tissues. Onset of ischemia triggers two reactions: Firstly, ischemia itself induces angiogenesis, that is sprouting of new capillaries. Endothelial progenitor cells from peripheral blood migrate to this site and differentiate to new endothelium. Secondly, arteriogenesis is initiated by increased perfusion in the remaining vessels. The shear stress leads to activation of monocytes and macrophages and subsequent transformation of preexisting collaterals to larger arterioles and arteries. The time course of development of collaterals is comparable in all models of sudden onset of ischemia. The idea, that only larger vessels maintain perfusion is highly convincing and supported by in vivo experiments [35,48,49]. Therefore, only arteriogenesis could functionally increase blood supply in ischemic areas. However, therapies which enhance angiogenesis are also able to improve cardiac function [74] and limb blood flow [61,62]. So far there is no resolution in the controversy as to how beneficial capillary and artery growth are and how great a role they play in collateral circulation. Validation of the successful development of collaterals due to therapy can be obtained by different approaches. Firstly, to the patient, only the improve576
ment of quality of life is important. Secondly, the physician is also interested in clinical parameters, for instance, blood flow or stress tolerance. Thirdly, direct imaging and quantification of the newly developed collaterals enables an analysis of local effects. Considering the impact of ischemic diseases of the heart and limbs on the individual as well as on the society, a treatment that is able to boost the collateralization process, is highly desirable.
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