Cross-talk between angiotensin II receptor types 1 and 2: potential role in vascular remodeling in humans.

Angiotensin (Ang) II exerts its important physiological functions through 2 distinct receptor subtypes, the type 1 (AT1) and type 2 (AT2) receptors.1 The AT1 receptor is expressed in diverse adult tissues, and its distribution is indicative of the fundamental role of Ang II on the regulation of cardiovascular and renal homeostasis. The predominant actions of Ang II, such as vasoconstriction, cellular proliferation and growth, renal sodium retention, and release of aldosterone, are linked to the activation of various signal-transduction pathways modulated by the AT1 receptor. Although the AT2 receptor is highly expressed in the fetus, its expression in adult tissues is low but increases in response to injury.2–5 It has been demonstrated that AT1 and AT2 receptors have counterregulatory interactions in the cardiovascular system.2 The AT2 receptor has been shown to exert an inhibitory effect on the growth-promoting action of the AT1 receptor.6 The cross-talk between AT1 and AT2 receptors has also been suggested to participate in the regulation of blood pressure. Ang II binding to the AT1 receptor activates G protein– coupled phospholipase C and inositol-1,4,5-triphosphate, which increases intracellular Ca levels resulting in vasoconstriction. On the other hand, Ang II binding to the AT2 receptor activates a counterregulatory pathway to induce vasorelaxation via activation of the kinin/NO/cGMP system.4,5 Indeed, it has been demonstrated that stimulation of the AT2 receptor induces vasorelaxation in mesenteric, uterine, renal, coronary, and cerebral resistance vessels, as well as in large conduit vessels.3–5 AT2 receptor null mice manifest slightly higher blood pressures at baseline than wild-type mice and enhanced acute blood pressure responses to lowdose Ang II infusion.7 In mice overexpressing AT2 receptors, the pressor response to Ang II infusion is significantly attenuated but is restored after blockade of AT2 receptors and/or blockade of NO synthase.8 Based on these studies, it has been proposed that AT2 receptor–mediated vasorelaxation may partly counteract AT1 receptor–mediated vasoconstriction and thereby contribute to the antihypertensive and/or vasoprotective effects of AT1 receptor blockers. Recent studies suggest that the upregulation of AT2 receptor expression and associated vasorelaxation may play an important role in vascular remodeling. Consistent with this notion, the study by Savoia et al9 in this issue of Hypertension provides exciting data demonstrating that small peripheral resistance arteries from hypertensive diabetic patients receiving long-term treatment with the AT1 receptor blocker valsartan exhibited enhanced AT2 receptor expression. This effect may be independent of blood pressure reduction, because AT2 receptor expression was not changed in the atenolol-treated patients with similar blood pressure control. Savoia et al9 demonstrated that, in human resistance vessels, AT2 receptors are not only present but functional. Indeed, AT2 receptor activation was unmasked in resistance vessels of valsartan-treated patients in which, when AT1 receptors were blocked, exogenous Ang II–induced vasorelaxation was blunted by the AT2 receptor blocker PD123319. However, in the resistance vessels from these AT1 receptor blocker– treated patients, the Ang II–mediated vasorelaxation was only 7.5%. This modest vasodilatory effect suggests that the role of the AT2 receptor in reducing blood pressure may be minimal, if at all. In the patients studied by Savoia et al,9 upregulation of AT2 receptors in the setting of AT1 receptor blockade was associated with an improvement in resistance artery remodeling that was independent of blood pressure effects. Thus, these results suggest that the AT2 receptor may play a significant role in vascular remodeling. AT2 receptors have been shown to be upregulated under conditions associated with cardiovascular tissue injury, such as common carotid balloon injury, myocardial infarction, heart failure, and hypertension.1,4,5 In the model of carotid balloon injury, treatment with valsartan significantly reduced intimal hyperplasia and concomitantly increased intimal, and to a lesser extent medial, AT2 receptor expression in the injured vessel but not in the contralateral normal vessel.4 These studies suggest that injury, as well as increased levels of Ang II associated with AT1 receptor blockade, is required for the upregulation of AT2 receptors in adult animals (Figure). Despite normalization of blood pressure and reasonable, although not perfect, control of glycemia, the diabetic patients studied by Savoia et al9 exhibited upregulation of the AT2 receptor in resistance vessels after 1 year of treatment with valsartan.9 What could have been the ongoing injury maintaining increased AT2 receptor expression: genetic predisposition to vascular injury or phenotypic changes in the vasculature that occurred during the time that the patients were hypertensive and/or hyperglycemic and that could not be reversed by the antihypertensive therapy over a period of The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Nephrology and Hypertension Section, Veterans Affairs Medical Center and Division of Nephrology and Hypertension and Vascular Biology Institute, University of Miami Miller School of Medicine, Miami, Fla. Correspondence to Leopoldo Raij, Nephrology–Hypertension Section, Veterans Affairs Medical Center, 1201 NW 16 St (Room A-1009), Miami, FL 33125. E-mail [email protected] (Hypertension. 2007;49:270-271.) © 2007 American Heart Association, Inc.