Physiological and Pathophysiological Functions of the AT ₂ Subtype Receptor of Angiotensin II

Abstract

Abstract-Angiotensin II exerts a potent role in the control of hemodynamic and renal homeostasis. Angiotensin II is also a local and biologically active mediator involved in both endothelial and smooth muscle cell function acting on 2 receptor subtypes: type 1 (AT 1 R) and type 2 (AT 2 R). Whereas the key role of AT 2 R in the development of the embryo has been extensively studied, the role of AT 2 R in the adult remains more questionable, especially in humans. In vitro studies in cultured cells and in isolated segments of aorta have shown that AT 2 R stimulation could lead to the production of vasoactive substances, among which NO is certainly the most cited, suggesting that acute AT 2 R stimulation will produce vasodilation. However, in different organs or in small arteries isolated from different type of tissues, other vasoactive substances may also mediate AT 2 R-dependent dilation. Sometimes, such as in large renal arteries, AT 2 R stimulation may lead to vasoconstriction, although it is not always seen. In isolated arteries submitted to physiological conditions of pressure and flow, AT 2 R stimulation may also have a role in shear stress-induced dilation through a endothelial production of NO. Thus, when acutely stimulated, the most probable response expected from AT 2 R stimulation will be a vasodilation. Therefore, in the perspective of a chronic AT 1 R blockade in patients, overstimulation of AT 2 R might be beneficial, given their potential vasodilator effect. Concerning the possible role of AT 2 R in cardiovascular remodeling, the situation is more controversial. In vitro AT 2 R stimulation clearly inhibits cardiac and vascular smooth muscle growth and proliferation, stimulates apoptosis, and promotes extra cellular matrix synthesis. In vivo, the situation might be less beneficial if not deleterious; indeed, if chronic AT 2 R overstimulation would lead to cardiovascular hypertrophy and fibrosis, then the long-term consequences of chronic AT 1 R blockade, and thus AT 2 R overstimulation, require more in-depth analysis. (Hypertension. 2001;38: 1150-1157.)

Can Angiotensin II Type 2 Receptors Have Deleterious Effects in Cardiovascular Disease?

“…In contrast, AT 2 is mainly present during fetal development (and is believed to have an essential role in physiological vascular development) but decreases rapidly after birth. 5,6 In adults, expression of AT 2 under normal conditions is largely restricted to the adrenals, kidneys, uterus, ovary, heart, and specialized nuclei in the brain, but it is upregulated in various pathological conditions associated with tissue remodeling or inflammation, including hypertension, heart failure, postmyocardial infarction, ischemia, and diabetes. 2,5,7 Multiple hormonal, cytokine, and metabolic factors are involved in upregulating AT 2 densities on cell surfaces.…”

“…The latter possibility is suggested by the finding in experimental studies that AT 2 -dependent NO production can only be observed after AT 1 blockade by losartan. 6,8 Thus, although AT 2 is present in the vasculature in adults, its distribution is not homogeneous and is subject to changes according to age, vessel type, and the presence of patholog-ical states. This raises the important question of their function in the cardiovascular system relative to that of AT 1 .…”

“…6 Rats subjected to a high-salt diet were found to exhibit a higher rise in BP in response to Ang II infusion when the selective AT 2 blocker PD123319 was coadministered. 11 In support of this finding, studies in AT 2 -knockout mice (ie, mice lacking AT 2 ) have shown that these animals have a higher BP and increased sensitivity to the pressor action of Ang II than wild-type mice.…”

Overexpression of angiotensin II type 2 receptor suppresses neointimal hyperplasia in a rat carotid arterial balloon injury model

“…Several molecules, including ERK1 and ERK2, have been involved in anG ii-induced VSMc proliferation (27). aT2r is abundantly expressed in VSMc of the fetal vasculature during late gestation (15). The expression of aT2r during fetal vasculogenesis influences the growth phenotype of VSMC via the modulation of the ERK cascade (28).…”

“…additionally, treatment with aT1r blockers (arBs) reduces the incidence of restenosis (12,13). aT2r is expressed abundantly in the fetal vasculature with rapid decline after birth, and is re-expressed in the adult vasculature under certain pathological cardiovascular conditions, such as vessel injury and inflammation (14,15). In injured vessels, aT1r is highly expressed, while aT2r is expressed at low levels (16).…”