How Structure, Mechanics and Function of the Vasculature Contribute to Blood Pressure Elevation in Hypertension

Journal Pre-proof How Structure, Mechanics and Function of the Vasculature Contribute to Blood Pressure Elevation in Hypertension Ernesto L. Schiffrin, MD, PhD PII:

S0828-282X(20)30075-1

DOI:

https://doi.org/10.1016/j.cjca.2020.02.003

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CJCA 3614

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Canadian Journal of Cardiology

Received Date: 31 October 2019 Revised Date:

2 February 2020

Accepted Date: 3 February 2020

Please cite this article as: Schiffrin EL, How Structure, Mechanics and Function of the Vasculature Contribute to Blood Pressure Elevation in Hypertension, Canadian Journal of Cardiology (2020), doi: https://doi.org/10.1016/j.cjca.2020.02.003. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Inc. on behalf of the Canadian Cardiovascular Society.

CJC-D-19-01629 R2 How Structure, Mechanics and Function of the Vasculature Contribute to Blood Pressure Elevation in Hypertension Ernesto L. Schiffrin, MD, PhD Lady Davis Institute for Medical Research, and Department of Medicine, Sir Mortimer B. DavisJewish General Hospital, McGill University, 3755 Côte-Ste-Catherine Rd., Montreal, Quebec, Canada H3T 1E2.

Word count: Total: 8550; Text: 4330; Brief summary: 76; Abstract: 278; Figures: 3; References: 140. Running head: Role of vasculature in BP elevation Phone, fax and e-mail: 514-340-7538, 514-340-7539 and [email protected]

Corresponding author: Ernesto L. Schiffrin, C.M., MD, PhD, FRSC, FRCPC, FACP Sir Mortimer B. Davis-Jewish General Hospital, #B-127, 3755 Côte-Ste-Catherine Rd., Montreal, PQ, Canada H3T 1E2 Fax: 514-340-7539 Phone: 514-340-7538 E-mail: [email protected]

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http://ladydavis.ca/en/ernestoschiffrin

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Brief summary Hypertension is multifactorial, but an important mechanism leading to blood pressure elevation is vascular remodeling and endothelial dysfunction of the microcirculation in younger individuals, and stiffening of large arteries in older individuals. In the presence of genetic susceptibility, excess salt intake, obesity, alcohol and perhaps gut microbiome dysbiosis activate the sympathetic nervous system, the renin-angiotensin-aldosterone system, the endothelin system, and inflammation and immunity, leading to vascular remodeling and injury and contributing to hypertension and its complications.

Abstract Large conduit arteries and the microcirculation participate in the mechanisms of elevation of blood pressure (BP). Large vessels play roles predominantly in older subjects, with stiffening progressing after middle age leading to increases in systolic BP found in most humans with aging. Systolic BP elevation and increased pulsatility penetrate deeper into the distal vasculature, leading to microcirculatory injury and remodeling, and associated endothelial dysfunction. The result is target organ damage in the heart, brain and kidney. In younger individuals genetically predisposed to high BP, increased salt intake or other exogenous or endogenous risk factors for hypertension including overweight and excess alcohol intake lead to enhanced sympathetic activity and vasoconstriction. Enhanced vasoconstrictor responses and myogenic tone become persistent when embedded in an increased extracellular matrix, resulting in remodeling of resistance arteries with a narrowed lumen and increased media/lumen ratio. Stimulation of the renin-angiotensin-aldosterone and endothelin systems, and inflammatory and immune activation to which may contribute gut microbiome

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dysbiosis as a result of salt intake also participate in the injury and remodeling of the microcirculation and endothelial dysfunction. Inflammation of perivascular fat and loss of anticontractile factors plays a role as well in microvessel remodeling. Exaggerated myogenic tone leads to closure of terminal arterioles, collapse of capillaries and venules and functional rarefaction, and eventually to anatomical rarefaction, compromising tissue perfusion. The remodeling of the microcirculation raises resistance to flow, and accordingly BP, in a feedback process that over years results in stiffening of conduit arteries and systo-diastolic or predominantly systolic hypertension, and more rarely, predominantly diastolic hypertension. Thus, at different stages of life and the evolution of hypertension, large vessels and the microcirculation interact to contribute to blood pressure elevation.

Key words: remodeling, stiffness, conduit arteries, resistance arteries, microcirculation, myogenic tone, endothelial dysfunction, vascular rarefaction, inflammation, immunity, gut microbiome

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Increased peripheral resistance is the hallmark of primary (previously called essential) hypertension.1 Increases in peripheral resistance result from changes in either large conduit arteries such as the aorta and its major branches, or in resistance vessels, which comprises the microcirculation, including small arteries, arterioles, capillaries and venules. Large arteries become stiffer with aging, resulting in elevated systolic blood pressure (BP).2 Small arteries have lumen diameters of 100-300 µm or less when relaxed, and arterioles less than 100 µm and typically have only one or two smooth muscle layers. Small arteries and arterioles constitute the major site generating approximately 70% of peripheral resistance.3 According to Poiseuille's Law, resistance varies inversely with the fourth power of the blood vessel radius. Accordingly, small decreases in the lumen will result in large increases in resistance to flow. Further downstream of arterioles, capillaries and venules may also participate in peripheral resistance through a process called rarefaction, whereby density of terminal arterioles, capillaries and venules in tissues is reduced.4 It has been suggested that rarefaction may contribute to blood pressure elevation by raising peripheral resistance by 15%.4

Structure and mechanics of large conduit arteries and their effect on BP BP rises with aging, especially after age 45 in men, and around 5-10 years later in women, often after menopause. This rise affects predominantly systolic BP, whereas diastolic blood pressure decreases. Cardiovascular risk seems to be mainly associated with the rise of systolic BP.5 There has been a suggestion that lower diastolic BP, especially below 70 mm Hg, is associated with increased risk of decreased coronary flow leading to myocardial ischemia (J-curve), particularly in patients with coronary artery disease.6 However, the enhanced risk of lower diastolic BP has been recently attributed to age5,7 and to the higher systolic blood pressure.5 These BP changes with aging

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are the result of vascular remodeling, mainly of large elastic arteries. Conduit elastic arteries such as the aorta and its large elastic branches of individuals beyond 45-55 years of age develop a process of arteriosclerosis of the media that leads to progressive stiffening of the vessel wall with aging. They increasingly develop outward hypertrophic remodeling as elasticity is altered by the effect of rising intravascular pressure, and degeneration and fragmentation of elastic fibers. As a result, elastic large vessels stiffen and their ability to distend during systole is progressively reduced as the forward pulse wave advances along the aorta,8 resulting in increased systolic BP. As pulse wave velocity accelerates because of the stiffened vascular wall, reflected waves9 generated at points of changing impedance arrive earlier, and rather than in diastole, they arrive to the proximal aorta in late systole, augmenting systolic blood pressure. This augmentation of systolic pressure partly erases the amplification of systolic pressure normally found distally from aorta to peripheral arteries, including the brachial artery, and the difference between peripheral and central pressure is reduced. As large vessels stiffen and wave reflection sites move distally, the increased pulsatility of large vessels penetrates deeper into the vasculature, inducing endothelial injury and remodeling of small vessels.8 Thus, it is likely that even when hypertension is predominantly systolic, resistance vessels contribute to blood pressure elevation, as well as impairing tissue perfusion and nutrient exchange. This results in microvascular damage in the coronary circulation, the brain and the kidney as well as the peripheral circulation of the limbs. For the changes in the microcirculation occurring as a consequence of large artery stiffening, and which affect nutrition and oxygenation of tissues and arrival of mediators and elimination of waste products of metabolism, see discussion below.

Microcirculation

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The vascular changes in the microcirculation involve reductions in lumen size that may be structural, mechanical and/or functional, and lead to increased energy dissipation and resistance to flow in small arteries and arterioles. Structural changes in small arteries with increased media-tolumen ratio correlate with forearm minimal vascular resistance, providing a functional significance to these changes.10 As well, there is rarefaction with decreased number of open terminal arterioles, capillaries and venules. All these changes contribute to raise peripheral resistance, leading to progressive elevation of blood pressure.

Structure of resistance arteries in hypertension The remodeling in hypertension of the structure of resistance (small) arteries, which are arteries of 100-300 µm in diameter, may take one of two forms: eutrophic remodeling or hypertrophic remodeling (Figure 1).11,12 Eutrophic remodeling involves a decrease in lumen diameter and outer diameter of small arteries, with conservation or decrease of the cross-sectional area of the media of the vessel and increase of the media-to-lumen ratio. Eutrophic remodeling is found in resistance arteries of rodent models of hypertension with an activated renin angiotensin-aldosterone system, such as 2-kidney 1 clip Goldblatt hypertensive rats13 and spontaneously hypertensive rats (SHR).1417

Eutrophic remodeling is also characteristic of small arteries of humans with stage 1 primary

hypertension.18-21 Hypertrophic remodeling, on the other hand, is characterized by an increase of the cross-sectional area of the media and a narrowed lumen as a result of encroachment of the thickened media on the lumen, with increased media-to-lumen ratio. Hypertrophic remodeling is found in rodent models with severe hypertension such as 1-kidney 1 clip Goldblatt hypertensive rats,21 deoxycorticosterone (DOCA)-salt hypertensive rats,22 and Dahl-salt sensitive hypertensive rats,23 in all of which the endothelin system is activated, which may contribute to the growth of the media

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both at the level of smooth muscle cells or expansion of the extracellular matrix.24 In humans, hypertrophic

remodeling

has

been

described

in

renovascular

hypertension

and

pheochromocytoma,25 in primary aldosteronism26 and hypertension associated with acromegaly27 and Cushing’s syndrome.28 "Remodeling" and "growth" indices can be used to approximate the relative contribution of eutrophic and hypertrophic remodeling, when varying degrees of one or the other is found to be present.29,30 Large arterioles (lumen diameter <100 and >20 µm) undergo remodeling similarly to small arteries.29

Rarefaction of the microcirculation and its effect on blood pressure The density of smaller terminal arterioles, capillaries and small venules is reduced in many tissues in hypertension. This reduction in vessel density is called rarefaction, which is another mechanism that increases peripheral resistance, contributing approximately 15% of the rise in vascular resistance found in hypertension.4 Rarefaction is initially transient and functional, as a result of enhanced myogenic tone, vasoconstriction and active collapse of the microvessels with obliteration of the lumen. With progression of hypertension, rarefaction becomes permanent and anatomical, with reduced arteriolar and capillary density, as described in different rodent hypertensive models of hypertension such as one-kidney one clip hypertensive rats,31 two-kidney one clip rats,32 DOCAsalt hypertensive rats,33 SHR34 and Dahl salt-sensitive rats,35 and in human hypertension.36 Interestingly, rarefaction may be an early change in human hypertension. Early studies have demonstrated an initial phase of hyperdynamic circulation in young adults with borderline hypertension.37,38 Associated to this stage of early borderline hypertension, several studies have reported in humans presence of rarefaction.39 Rarefaction in humans with established hypertension had already been reported by Short in a very early autopsy study.40 The possible sequence of these

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changes may be increased sympathetic activity due to a higher set point of BP, what Stevo Julius has termed “the higher BP seeking behavior of the central nervous system”,41 leading to an increase in cardiac output and a hyperdynamic circulation.37,38 However, this later evolves into established hypertension associated with elevated peripheral resistance. The transition occurs as remodeling of small arteries and arterioles, and microcirculatory rarefaction increase peripheral vascular resistance over the course of hypertension as a result of enhanced myogenic tone and vascular reactivity and eventual remodeling of the resistance circulation as discussed below, upon which sympathetic tone decreases.

Mechanisms of remodeling of the vascular system An important question that needs to be answered is whether the phenotype of resistance arteries in hypertension is a consequence of hemodynamic, endocrine, inflammatory and immune, paracrine or autocrine factors present or activated by BP elevation, or a primary genetically determined abnormality leading to the molecular, cellular, structural and functional characteristic vascular changes found in hypertension. This will only be summarily discussed, as it is addressed in other manuscripts in this compendium. Hemodynamic effects and the role of the sympathetic nervous system especially in borderline hypertension have already been discussed, and the mechanism whereby increased perfusion pressure results in remodeling of the resistance vessels and microcirculation is addressed below. The renin-angiotensin-aldosterone system plays a role in remodeling in experimental and genetic hypertension in rodents42,43 and in humans,20,44,45 in the latter as demonstrated in studies using blockers of these systems. The role of the endothelin (ET) system in BP elevation and remodeling of small arteries was first demonstrated by the enhanced expression of ET in the endothelium of ET-1 in DOCA-salt46 and aldosterone-induced

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hypertension,43 as well as in one-kidney one clip Goldblatt hypertension.47 Furthermore, endothelin antagonists lowered blood pressure and corrected vascular remodeling in mineralocorticoid hypertension in rodents.48 However, spontaneously hypertensive rats (SHR) did not exhibit overexpression of ET in the vasculature46 and did not respond to endothelin antagonists with BP lowering or correction of vascular remodeling.49 The role of ET-1 has been extended by our demonstration of microcirculatory remodeling and endothelial dysfunction occurring with transgenic overexpression of human ET-1 in endothelium in mice, either congenitally24 or inducibly.50,51 As well, in humans overexpression of ET-1 in endothelium of small arteries was shown in stage 2 hypertension.52 We and others have also demonstrated a role for inflammation and immunity in the processes leading to remodeling of the vasculature in rodent models contributing to BP elevation. Macrophages, which are part of the innate immune system, were shown to be critical for angiotensin II-induced small artery remodeling, endothelial dysfunction and BP elevation.53,54 T effector lymphocyte deficiency is associated with reduced vascular remodeling and BP elevation in mice infused with angiotensin II.55 On the other hand, adoptive transfer of T regulatory lymphocytes, which are anti-inflammatory through production of interleukin (IL)-10 and transforming growth factor (TGF)-β lowers BP and corrects endothelial dysfunction in mice receiving angiotensin II56 and also corrects vascular remodeling in mice infused with aldosterone.57 γδ T cells, which are unconventional innate-like lymphocytes that can produce interferon-γ and IL17, have also been show to play a role in both BP elevation, small artery remodeling and endothelial dysfunction in mice infused with angiotensin II and on BP regulation in a human cohort.58 Salt may contribute to activate the immune system, and specifically Th17 lymphocytes in the intestinal wall, via changes in the gut microbiome,59 leading to enhanced low-grade inflammation that contributes

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to blood pressure elevation and vascular injury. The inflammatory response may affect perivascular fat, normally a source of anti-contractile agents including adiponectin, leading to enhanced vasoconstriction and vascular remodeling.60,61 The genes participating in the induction of the vascular changes associated with hypertension are in the process of being identified by genome wide association studies (GWAS) as well as with candidate gene approaches. Many relate to the vasculature and particularly to the endothelium.62,63 MicroRNAs, small non-coding RNAs of around 20 base pairs that regulate gene expression, may be important in the remodeling of small arteries. We recently investigated microRNAs expressed in resistance arteries of angiotensin II-infused mice to determine whether they could contribute to modulation of BP and vascular remodeling.64 We identified, using an unbiased approach (microRNA and mRNA sequencing with molecular interaction analysis), a microRNA-transcription factor co-regulatory network involved in vascular injury in mice made hypertensive by 14-day angiotensin II infusion. A candidate gene approach identified up-regulated miR-431-5p encoded in the conserved 12qF1 (14q32 in humans) miRNA cluster, whose expression correlated with BP, and which is up-regulated in human atherosclerosis. Gain- and loss-of-function in human vascular smooth muscle cells demonstrated that miR-431-5p regulates in part gene expression by targeting Ets homologous factor. In vivo miR-431-5p knockdown delayed angiotensin II-induced BP elevation and reduced vascular remodeling in mice, which confirmed its potential role in hypertension and vascular injury. In eutrophic remodeling, the vascular wall is restructured with smooth muscle cells aligned more closely encircling the lumen without any change in the volume of the media or the stiffness of the vessel wall. A combination of growth and apoptosis,65-67 the latter in the periphery of the artery wall, could lead to the reduced outer diameter of the vessel, with inward growth encroaching on the

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lumen and reducing its diameter. Changes in extracellular matrix components and adhesion molecules could result in rearrangement of smooth muscle cells and restructuring of the vascular wall found in these vessels.68 The vasoconstricted state due to the increased myogenic tone becomes embedded in the newly deposited extracellular matrix in the media and adventitia consisting of collagen and fibronectin, with the characteristic remodeling of the vessel wall. Integrins link components of the extracellular matrix and the cytoskeleton and play roles in signal transduction. We have proposed that changes in these anchorage sites are involved in the rearrangement of smooth muscle cells in remodeled small arteries in hypertension, and could be involved in the persistently narrowed lumen and embedding of the vasoconstricted state of small arteries via enhancement of cell-matrix attachments and distribution on the surface of smooth muscle cells. In arteries of SHR, expression of αvβ 3 and α5β1 integrins in mesenteric arteries increase as they reach adulthood together with increases in the volume density of collagen.69 α5 integrins and fibronectin, which is their ligand, have been reported by other authors as well to be increased in aorta of SHR.70 Hypertrophic remodeling is associated with growth of the media with narrowing of the lumen. Increased smooth muscle cell number71,72 and/or volume73,74 are also present, with increased collagen and fibronectin deposition.

Extracellular matrix glycoproteins co-localize with

proliferating smooth muscle cells and could play a role in the proliferative response. Fibronectin75 and osteopontin76 can modulate hypertrophic remodeling.

Osteopontin is an RGD-containing

protein that adheres to vascular smooth muscle cells through αvβ3 integrins,77 and is associated with the synthetic smooth muscle cell phenotype found in the vascular wall,78 contributing to extracellular matrix deposition, a major component of the remodeling of blood vessels in hypertension.68,69,79-82

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Both eutrophic and hypertrophic remodeling are influenced by agents such as angiotensin II, whose actions are enhanced in hypertension.20,73 Angiotensin II stimulates the deposition of both fibrillar and nonfibrillar components of the extracellular matrix.83,84 Nonfibrillar matrix components include proteoglycans that carry glycosaminoglycans synthesized by vascular smooth muscle cells in response to growth factors,85 which modulate proliferation and differentiation,86 and whose synthesis is increased in the vasculature of SHR.87 Collagen type I and type III are the major constituents of the intima, media, and adventitia, and are also found together with collagen type IV and V on endothelial and smooth muscle cell basement membranes.88-90 What are the mechanisms for increased abundance of extracellular matrix proteins in resistance arteries in hypertension? Beyond the effect of increased biosynthesis of extracellular matrix components, the activity of matrix metalloproteinases (MMP), including MMP-1 and MMP3, is reduced in serum of SHR90,91 and in human primary hypertension.92,93 Thus, enhanced synthesis of type I collagen is not counterbalanced by collagen degradation by MMPs. In aorta and mesenteric arteries of stroke-prone SHR, gene expression of types I, III, and IV collagen was upregulated. MMP-1 and MMP-3 activity was decreased in the mesenteric arterial bed of young SHR before hypertension became established, leading to the progressive accumulation of fibronectin and proteoglycans found later in the adult SHR.85,87 In adult SHR, the activity of proMMP2 and activated MMP-2 was reduced in mesenteric arteries, facilitating accumulation of types IV and V collagen and fibronectin.94-96 MMP inhibition has been shown to prevent elastin degeneration, collagen deposition, and increases in BP by its effects on the monocyte chemotactic peptide-1/TGF-β1/ET-1 proinflammatory signaling axis.97

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Mechanical abnormalities of resistance arteries that influence BP The stiffness of the artery wall is increased in rodent models of hypertension and in patients with primary hypertension. This change may increase resistance to blood flow by reducing the distensibility of the vessel wall during systole. The stiffness of mesenteric resistance arteries in SHR may be reduced initially,98,99 followed later by increased stiffness of wall components, with reduced distensibility as collagen deposition is enhanced.68 Large second order cerebral small arteries from SHR-sp were stiffer than vessels from WKY rats, whereas smaller third order arteries exhibited decreased stiffness.29,98 In Dahl-salt sensitive rats100 and in DOCA-salt hypertensive rats,101 small artery stiffness was not enhanced. In humans, progressive arterial stiffening was found as individuals age or develop hypertension.102 Subcutaneous small arteries from hypertensive patients exhibited normal stiffness compared to vessels from normotensive individuals in some studies,103 whereas in others decreased stiffness was reported.104 The latter finding seemed agerelated, as other groups of older subjects showed no difference in the stiffness between vessels of hypertensive and normotensive individuals.81,103 We have proposed that early in the disease collagen fibers may be recruited at higher distending pressures in small arteries from stage 1 hypertensive patients than in vessels from normotensive subjects, whereas later, compliance of resistance arteries in hypertensive individuals may be reduced in part due to the smaller lumen and greater collagen/elastin ratio, and the engagement of collagen fibers and resulting tensing of the collagen jacket at earlier portions of the pressure curve.104 In fact, decreased wall stiffness was demonstrated in cerebral arterioles from stroke-prone SHR,98,105,106 which could be attributed to increased elastin content.107 In peripheral resistance arteries, vessel wall stiffness was increased in SHR with increased volume density of collagen and/or collagen/elastin ratio.68,80 In subjects with

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primary hypertension in who we showed vascular stiffness to be initially decreased despite an increased collagen/elastin ratio,81 proteoglycans could be responsible for some of the changes in stiffness of resistance arteries. Interactions between extracellular matrix proteins, smooth muscle cells, and adhesion molecules may be critical for cell attachment to fibrillar components of the extracellular matrix and regulate the degree of stiffening, explaining differences reported in the literature.

Functional abnormalities of resistance arteries in hypertension Abnormal resistance artery function in hypertension may increase peripheral resistance by reducing lumen diameter, due to enhanced constriction. Early in experimental hypertension enhanced myogenic tone107 and increased response to norepinephrine have been reported.14,15,17 Impaired endothelium-dependent relaxation has been a functional abnormality considered prototypical of hypertension, although not always present, especially in early hypertension.104 It can also contribute to stiffening and vasoconstriction, including at the level of large arteries.108 A reduction in acetylcholine-induced and flow-mediated vasodilatation has been repeatedly reported in rodent and human resistance arteries,104,109-111 and thus reduced vasodilation could contribute to BP elevation. Vasoconstriction has classically been described as a mechanism for the increases in vascular tone in hypertension,112 in both human vessels17 and in experimental hypertensive rodents.14 Interestingly, vasoconstrictors such as endothelin-1 and vasopressin and even norepinephrine often induce reduced vasoconstriction compared to normotensive controls,3,18 indicating that the enhancement in vasoconstriction in hypertension may reflect the effects of the Law of Laplace, whereby amplification of vasoconstrictor responses is caused by structural or mechanical reduction of lumen diameter.113-116 Some investigators have argued against a structurally-based exaggerated

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vasoconstriction,117,118 which has been contradicted by others.119 Augmented vasoconstriction has also been reported in responses to angiotensin II in human blood vessels.3,18 Reactive oxygen species production by smooth muscle cells from resistance arteries of hypertensive humans is enhanced in response to angiotensin II, and this may relate to coupling of the AT1 angiotensin receptor to signaling events with increased calcium entry and release in smooth muscle cells from vessels from experimental animals and humans with hypertension,120-123 and could contribute to the inflammatory response we report above. The extracellular matrix may participate in the mechanisms of abnormal function of resistance arteries in hypertension.

Peptides carrying the minimal integrin-binding sequence

arginine-glycine-aspartate (RGD) induce rapid, endothelium-dependent and slower, endotheliumindependent relaxation of rat aortic rings, mediated by binding to αvβ3 integrins124,125 via reduction of intracellular calcium in vascular smooth muscle cells,126 mediated by K+ channels127 or L-type Ca2+-channels, the latter also by binding to α5β1 integrins.128 RGD-containing peptides may also cause endothelium-dependent vasoconstriction mediated by ET-1 in rat skeletal muscle arterioles.129 Contraction of smooth muscle has been demonstrated to increase proportionally to amounts of fibronectin it is in contact with,130 indicating that when fibronectin70 or the fibronectin receptor α5β1 integrin69 are increased, occupancy of the latter may increase contractility and vascular resistance. Inhibition of vascular MMP-2 in rat mesenteric arteries has demonstrated the vasoconstrictor effects of big ET-1, which arises from MMP-2-mediated cleavage to release the vasoconstrictor peptide ET-1[1-32].131

Relation of the Vascular Phenotype to Evolution of Different Subtypes of Hypertension (Natural History of Hypertension)

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Evaluation of the Framingham Study findings have provided novel views of the natural history of hypertension,132 and potentially the contribution of blood vessels to different stages of hypertension or elevation of blood pressure and presence of different phenotypes. Using data from the cohort studied between 1955 and 1965, the risk of developing different subtypes of hypertension (prehypertension, isolated systolic hypertension, isolated diastolic hypertension, systo-diastolic hypertension) after 10 years was compared with the group with optimal BP (<120/80). Interestingly, this evolution occurred when drug therapy was mostly unavailable. Subjects with normal BP (>120/80 and <130/85) had similar risk of developing isolated diastolic hypertension (>3-fold), isolated systolic hypertension (>3-fold), or systo-diastolic hypertension (>3-fold). Subjects with high-normal BP (>130/85 and <140/90) were eight times more likely than those with optimal BP to develop systo-diastolic hypertension, and five times more likely to develop isolated systolic hypertension. Their relative risk of developing isolated diastolic hypertension was however low. Accordingly, pre-hypertension as defined by JNC 7, had elevated risk of evolving toward both systo-diastolic hypertension and isolated systolic hypertension. We have proposed that small degrees of BP elevation could lead to changes in timing of wave reflection because of altered impedance in remodeled small arteries. Reflected waves returning proximally earlier could result in systolic augmentation.2 As the conduit vessels stiffen due to the systolic BP elevation with increased collagen and/or calcification, Windkessel function of these vessels is lost. Thus, proximal large arteries can store more energy during systole and recoil during diastole, resulting in higher central systolic pressure, lower central diastolic pressure, increased pulse pressure and isolated systolic hypertension (Figure 2). Subjects with isolated diastolic hypertension at baseline were mostly male obese smokers, and therefore at high cardiovascular risk. Thus, isolated diastolic hypertension is not benign.

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isolated diastolic hypertension patients had a 23-fold higher risk than subjects with optimal BP to develop systo-diastolic hypertension. Severe small artery remodeling in subjects with isolated diastolic hypertension could lead as well through early wave reflection to augmentation of pulse pressure and isolated systolic hypertension. Subjects with isolated systolic hypertension at baseline were at 7-fold higher high risk of developing systo-diastolic hypertension than optimal BP subjects. Large artery stiffening through increased pulsatility penetrating deep into the microcirculation could result in small artery injury and remodeling (Figure 2), raising diastolic BP. Indeed, media-to-lumen ratio of small arteries correlated with pulse pressure in elderly hypertensive subjects with a mean age of 70 years.133 We have shown similar results in hypertensive patients with a mean age of 55 years.134 Also, in a cohort of hypertensive patients investigated by Mitchell et al.,135 aortic pulsatility correlated with forearm vascular resistance. This suggests an interaction between large arteries and the microcirculation, with increased pulsatility transmitted downstream eliciting potentially endothelial dysfunction and reduced vasodilation, enhanced vasoconstriction through myogenic tone, and small artery remodeling. The latter, through changes in impedance resulting from remodeling, could accelerate reflected wave return, worsening large artery stiffening and increasing pulse pressure.136

Does vascular remodeling of large or small arteries and the microcirculation contribute to the development of elevated BP in primary hypertension? The preceding paragraph describes how different subtypes of hypertension may evolve from prehypertension, and one into another, and their potential relationship with the vasculature. One additional aspect is the role of baseline aortic diameter. Data from different cohorts has suggested an initiating role for a small aortic diameter in subjects at risk of developing hypertension.137 This

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could be followed by increased stiffness of conduit arteries, contributing as well to the lower diastolic BP associated with aging. In younger individuals, does small artery remodeling through increased peripheral resistance contribute to elevated diastolic BP? Minor BP elevations induced by increased sympathetic activity and increased cardiac output could lead to endothelial dysfunction, decreased vasodilation, increased myogenic tone and small artery remodeling. The latter through an amplifying effect on BP could then feedback into a vicious circle that slowly over many years nonlinearly results in progressive BP rise. However, stopping antihypertensive medication in experimental animals has been associated with a more rapid rise in BP in those animals in which vascular remodeling had been corrected.138 Cross-transplantation experiments in AT1a receptordeficient mice have shown that the AT1a receptor in the kidney and in extrarenal tissues, including the systemic vasculature, play a role in BP elevation,139 strongly suggesting a role for peripheral small arteries in hypertension. In humans, correction of remodeling of the vasculature has accompanied lowering of BP. These variables are difficult to dissociate, although beta blockers, particularly atenolol, may lower BP without improvement of blood vessel structure or function20 whereas renin-angiotensin blockade both lowers BP and corrects remodeling of small arteries.20,44 A cause-effect relationship remains however difficult to establish unambiguously. Notwithstanding these questions about the role of blood vessels in BP elevation, correcting the vascular phenotype early in the disease could allow preventing incident hypertension,140 or the increasing severity of BP elevation and its complications.

CONCLUSIONS In conclusion, endothelial or smooth muscle cell changes, adhesion molecules, and extracellular matrix components contribute to molecular, structural, mechanical or functional changes that

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characterize the vascular phenotype in hypertension, resulting in stiffening of large arteries and reduced lumen size of small arteries and arterioles, and rarefaction of terminal arterioles, capillaries and venules, leading to increased peripheral resistance, the hallmark of primary hypertension. As a result, tissue nutrition, mediator access, gas exchanges and removal of waste products is compromised, contributing to target organ damage. A cross-talk between stiffening of large conduit arteries and remodeling of small resistance vessels (Figure 2) contributes to progressive increases in resistance to flow and elevation of blood pressure, triggered by activation of the sympathetic nervous system, the renin-angiotensin-aldosterone system, the endothelin system, and other vasoactive agents, with an inflammatory and immune component associated with salt-induced gut microbiome dysbiosis that together lead to the vascular changes found in hypertension (Figure 3). Funding sources The author’s work was supported by Canadian Institutes of Health Research (CIHR) First Pilot Foundation Grant 143348 and a Canada Research Chair (CRC) on Hypertension and Vascular Research from the CRC Government of Canada/CIHR Program.

DISCLOSURE None.

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FIGURE LEGENDS Figure 1. Schematic drawing depicting eutrophic remodeling and hypertrophic remodeling of resistance arteries in hypertension, and potential agents playing roles in determining the nature of remodeling. As hypertension progresses, it is possible but unproven that eutrophic remodeling may evolve toward hypertrophic remodeling under the combined influence of angiotensin II ± endothelin-1, other growth factors, inflammatory and immune mechanisms, the sympathetic nervous system, and high blood pressure itself. Reproduced with permission from Schiffrin EL.12 Figure 2. Natural history of HTN according to the Framingham Study: Role of the vasculature, based on Franklin et al.124 Risk of different subtypes of hypertension evolving into other subtypes and the potential role that the vascular phenotype may contribute to this evolution, thus determining the natural history of these different subtypes. IDH, isolated diastolic hypertension; ISH, isolated systolic hypertension; SBP, systolic blood pressure; and SDH, systo-diastolic hypertension. Reproduced with permission from Schiffrin EL.2 Figure 3. Summary diagram of different mechanisms contributing to remodeling of the vasculature and its role in blood pressure elevation.

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Figure 1 Normotensive

Hypertensive

Hypertrophic Remodeling Media/lumen CSA (endothelin)

Eutrophic Remodeling Media/lumen = CSA (angiotensin II)

Figure 2

Natural history of HTN according to the Framingham Study: Role of the vasculature

ISH

Prehypertension Small artery remodeling (preHTN) → reflected waves → ↑SBP → ISH

SDH

IDH

Small artery remodeling (IDH) → reflected waves → ↑SBP → SDH

SDH

ISH ↑SBP → Small artery remodeling → SDH

Salt Genes

Central nervous system

Renin-angiotensin system

Endothelin system

Sympathetic nervous system Catecholamines Aldosterone Damage-activated molecular patterns? Oxidative stress

Inflammation Immune system activation

Cardiac output Cytokines Chemokines

Microbiome dysbiosis

Cardiac output

Vasoconstrictor responses Myogenic tone Endothelial dysfunction and vasodilatation Smooth muscle proliferation and vascular remodeling Collagen and fibronectin Vascular stiffening αvβ β3 integrins, glycosaminoglycans Matrix metalloproteinases Rarefaction of terminal arterioles and capillaries

Large artery stiffness Systolic BP Pulsatile energy to the periphery Resistance to blood flow Diastolic BP

End-organ damage

Hypertension

Stroke Myocardial infarction Heart failure Chronic kidney disease