(Hypertension. 2007;49:1.)
© 2007 American Heart Association, Inc.
Hypertension Highlights |
From the Division of Cardiovascular and Endocrine Sciences, Faculty of Medical and Human Sciences, University of Manchester, United Kingdom.
Correspondence to Anthony M. Heagerty, Division of Cardiovascular and Endocrine Sciences, Faculty of Medical and Human Sciences, University of Manchester, Core Technology Facility, 46 Grafton St, Manchester, M13 9NT United Kingdom. E-mail tony.heagerty{at}manchester.ac.uk
| Introduction |
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To understand how hypertension produces the above nonhypertrophic changes in small arteries, one must look at the role of the resistance vasculature. At physiological pressures, these vessels typically exhibit a level of contraction (myogenic tone) independent of neurohormonal influences. This response enables blood vessels to constrict or dilate in response to changes in pressure. This process, known as the myogenic response, is only observed in smaller resistance arteries, which mediate autoregulation of blood flow and stabilize capillary pressure.5
Hypertrophy is observed in vessels that do not possess myogenic tone, whereas, in smaller resistance arteries, an initial increase in pressure will bring about increased myogenic constriction, which, if prolonged, will lead to inward eutrophic remodeling and/or a reduced arterial distensibility.6 This structural difference between large conduit and resistance arteries is apparent in many models of hypertension, for example, in a hypertensive model bought on by chronic NO synthase inhibition.7 In addition, the magnitude and duration of an increase in intraluminal pressure plays a role in determining the remodeling process.8 It has become evident that the extracellular matrix (ECM) integrincytoskeleton axis plays an essential role in the mechanosensory apparatus, which enables VSMCs to detect and respond to changes in intraluminar pressure, allowing eutrophic inward remodeling of resistance arteries in hypertension.
| Eutrophic Inward Remodeling |
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In our studies of the well-characterized TGR(mRen2)27 rat, which develops hypertension from 4 weeks of age, we found that eutrophic inward remodeling occurs from 4 weeks and depends on integrin
Vß3, a multifunctional ECM receptor (Figure 1).9,15 Hypertrophy also begins to appear at between 6 and 8 weeks of age.9 Hypertrophy and a reduced distensibility are also observed in cerebral vessels of the stroke-prone spontaneously hypertensive rat when the animals are given a high-salt/low-protein diet compared with the spontaneously hypertensive rat, before strokes occur.16 The spontaneously hypertensive rat, in contrast, is stroke resistant, and cerebral vessels from young spontaneously hypertensive rats display eutrophic inward remodeling compared with the Wistar-Kyoto rat but exhibit a reduced distensibility in adulthood.3 Finally, subcutaneous small arteries of patients with type 2 diabetes and microalbuminuria exhibit hypertrophy, which coincides with an impaired myogenic response irrespective of whether there is hypertension or not.4,17,18 Therefore, current evidence suggests that an increase of hypertrophy might ensue as a compensatory mechanism8 when eutrophic remodeling is inadequate to normalize wall stress, because the stimulus for remodeling (ie, vasoconstriction) is impaired.
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| Integrins, Mechanotransduction, and Cytoskeletal Reorganization |
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Vß3 and
5ß1 indirectly regulate the myogenic response by control of Ca2+ flow through ion channels.
5ß1 is responsible for the initial Ca2+ influx required to establish vessel tone and
Vß3 to mediate force maintenance by a Ca2+ sensitization of contractile components.1921 These integrins can form complexes that regulate cytoskeletal dynamics to maintain a vascular myogenic force at a given pressure. This is abrogated on cytoskeletal disruption.22,23 Cytoskeletal proteins, such as heat-shock protein 27, activated by RhoA/Rho-kinases, have been shown to regulate myogenic contractility.24 It is now clear that RhoA signaling plays a central role in both calcium sensitization pathways and regulation of actin dynamics in resistance artery remodeling (elegantly reviewed in references2526). In contrast to molecular signaling mechanisms behind the vascular myogenic response, relatively few data are available on the role of integrins and the underlying biochemical pathways of the next stage of vascular adaptation to hypertension that is the migration of VSMCs toward a narrowed lumen. | Integrins and VSMC Migration |
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Integrin
Vß3 is necessary for the pressure-induced inward remodeling process9; however, the biochemical mechanisms underlying this process are sketchy. Src, a component associated with mechanotransduction, is thought to be the initial messenger after integrin activation at the onset of remodeling (Figure 2). It has been shown that elevation of intraluminal pressure of resistance arteries induces Src-Y418 phosphorylation to activate its downstream target FAK, resulting in an accumulation of phosphorylated FAK (Y397).30 Targeting of
V integrins with RGD peptides specifically interferes with FAK activation31 and provides further evidence for a role of Src/FAK pathways in the onset of migration or "sliding" of VSMCs in eutrophic remodeling. Finally, migration of VSMCs in resistance arteries is terminated by fixation of ECM components by surface transglutaminases.32 Transglutaminase is capable of rapidly forming highly stable cross-links of ECM proteins, including collagen, osteopontin, and fibronectin, especially near sites of adhesion, where integrins cluster.33 It is a fast and stable way of fixing cells in place in a remodeled orientation and is replaced over time by gradual matrix turnover.32 One such mechanism by which matrix turnover and stability of other ECM components is facilitated is by fibronectin polymerization into an existing matrix through a caveolin-1dependent process.34
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Perspectives
A central role for integrins seems to have been clearly established when it comes to the maintenance of myogenic integrity in the resistance vasculature. The breakdown of autoregulation and the loss of a physiological myogenic response to pressure seems to be involved in increasing pathological blood flow to target organs with the resulting loss of cellular function and tissue damage. It remains uncertain as to whether correction of hypertension is inevitably associated with the restoration of the myogenic response or complete protection of vital organs. Data from the vasculature of normotensive diabetics would suggest that this is not the case. The specific identification of 2 integrins that seem to have a crucial role in not only maintaining adequate myogenicity but also being responsible for the physiological response to pressure, namely, eutrophic inward remodeling, means that there is the tantalizing possibility of developing new therapeutic molecules to enhance their activity, thereby reinforcing the physiological responses to pressure, namely, eutrophic remodeling and the ability to respond to high-pressure loads with vasoconstriction. In addition to conventional antihypertensive therapy, it may well be that the future of blood pressure treatment centers around maintaining normal vascular function in this way.
| Acknowledgments |
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Sources of Funding.
We thank the Wellcome Trust and British Heart Foundation for supporting our research. Our clinical studies are carried out in the Manchester Wellcome Trust Clinical Research Facility.
Disclosures
None.
Received May 26, 2006; first decision June 13, 2006; accepted November 1, 2006.
| References |
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