doi: 10.1161/ATVBAHA.107.155978
© 2008 American Heart Association, Inc.
Editorials |
Angiotensin II and New Vessel Formation
Aiming for the Right Oxidative Window
From the Department of Medicine, Division of Cardiology, Emory University School of Medicine and the Atlanta V.A. Medical Center, Atlanta, Ga.
Correspondence to W. Robert Taylor, MD, PhD, Cardiology Division, Emory University School of Medicine, 1639 Pierce Drive, Suite 319 WMB, Atlanta, GA 30322. E-mail wtaylor{at}emory.edu
New vessel formation is a critical component of homeostatic adaptation to ischemia and infarction. Well-developed collateral circulation confers a better prognosis in patients with acute myocardial infarction and stable coronary artery disease.1,2 However, approaches used to manipulate vessel growth in animal models have had limited success when translated into new therapies for patients with cardiovascular disease.
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As an agonist of the NADPH oxidase, angiotensin II (Ang II) has long been recognized as a prooxidant, a feature that is central to its role as a proinflammatory agent in cardiovascular pathophysiology.3 Like other proinflammatory stimuli,4 Ang II has been reported to have an almost paradoxical effect in inducing new vessel formation. The growth-stimulatory effects of Ang II on the vasculature are well documented and potentially entirely consistent with a positive effect on new vessel formation. However, the ultimate effect of Ang II on new vessel formation is controversial as it has been reported to both stimulate and inhibit vessel growth.5 One possible explanation for these conflicting data includes the differences in the pharmacokinetic and pharmacodynamic profiles of the various therapeutic agents that have been tested. Specifically, tissue affinity has been proposed to influence the potential role that angiotensin converting enzyme (ACE) inhibitors play in regulating the formation of new vessels. Those with high tissue affinity appear to be more likely to promote vascularization.6 Other potential mitigating factors include Ang II regulation of vascular endothelial growth factor expression and the effects of ACE inhibition on bradykinin levels. In the latter case, it has been suggested that the proangiogenic effects of ACE inhibitors occur through the bradykinin B2 receptor pathway.7 A final and very important consideration in reviewing the conflicting reports on the role of the renin angiotensin system in new vessel formation is the relative contributions of arteriogenesis and angiogenesis to the various experimental models.8 These distinct processes proceed in response to different biological cues and likely have very dissimilar molecular and cellular mechanisms.
In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Reed et al9 propose that the reported disparate effects of Ang II on collateral vessel formation can best be explained by examining the context in which collateral formation was studied. They propose that in the setting of low oxidative stress, Ang II promotes new vessel formation whereas in the setting of elevated oxidative stress, Ang II is inhibitory. In support of this hypothesis, they measured coronary collateral flow in response to repetitive ischemia in WKY rats (which are free of vascular disease) and in JCR rats which have a high basal oxidative stress and a phenotype similar to the metabolic syndrome seen in humans. Using these models, they showed that AT1 receptor blockade inhibited collateral flow in the setting of low background oxidative stress (WKY rats) but enhanced it in the setting of high background oxidative stress (JCR rats). Similarly, they showed in WKY rats that low dose Ang II increased collateral vessel flow whereas high dose Ang II was inhibitory. In addition, they provided evidence that differential activation of the signaling intermediates p38 MAP kinase and Akt plays a role in this paradox. Critical to their conclusion are previous data generated by the same group indicating that very high or very low levels of myocardial reactive oxygen species inhibited adequate coronary collateral growth in a rat model of transient repetitive ischemia.10
These observations also raise some very important questions that are central to our further understanding of this hypothesized "oxidative window." First and foremost, it is not clear whether angiogenesis or arteriogenesis is the processes targeted by Ang II. This is a critical distinction not only in terms of experimental models but also in the application of this proposed mechanism to human disease states. In these studies it is in fact difficult to determine the relative contributions of new vascular growth per se versus opening of preexisting collateral vessels. It is also uncertain which cells are the targets of Ang II. Conceivably, endothelial cells, smooth muscle cells, vascular progenitor cells, monocytes, and other inflammatory cells could all be impacted by Ang II stimulation and could intern modify the formation of functional collateral vessels. Finally, exclusive causality of reactive oxygen species in this set of studies is open for discussion. Ang II has many effects that are not mediated by reactive oxygen species that may also contribute to vascular growth. Despite these unanswered questions, the central finding of this article, that the effects of Ang II of coronary collateral flow are dependent on the basal level of oxidative stress warrants careful consideration and future study.
Reed et al have provided a crucial contribution to our current understanding of the role of Ang II in the formation of new vessels in the setting of ischemia. They suggest that the paradoxical effects of Ang II on new vessel formation are explained by the fact that Ang II signaling may have different effects on new vessel formation depending on the basal vascular oxidative stress. There appears to be an oxidative window between the "too low" and "too high" oxidative states which favors collateral vessel formation. Importantly, this concept is applicable to other disease states where elevated levels of reactive oxygen species would tip the balance of the effects of Ang II on collateral growth in favor of an inhibitory effect. These findings have obvious and potentially important implications for our understanding of pharmacological approaches to the treatment of occlusive vascular disease and their application to human disease.
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Acknowledgments |
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Disclosures
None.
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References |
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Related Article:
Arterioscler Thromb Vasc Biol 2008 28: 61-67.
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