K012 Pharmacological blockade or genetic deletion of AT2R abolishes flow-induced structural remodeling in rat and mice resistance arteries in vivo

Abstract

The renin—angiotensin system (RAS) plays a major role in regulating the cardiovascular system. Angiotensin II (AngII), the main effector of the RAS, is involved in both endothelial and smooth muscle cells functions, acting by two receptors, type 1 (AT1R) and type 2 (AT2R). If the role of the AT1R has been widely investigated in vivo and in vitro, the role of the AT2R remains controversial. It is admitted that AT2R induces vasodilation and possesses anti-proliferative properties. Nevertheless, recent studies have shown that the AT2R is vasoconstrictor in hypertension and has proliferative effects in tumors. AT2R has a role in vascular reactivity to flow (shear stress) and in cell growth and migration. Moreover, the AT2R decreases MMP-2 and increases elastin. Thus we hypothesized that changes in vascular wall mechanical strain, extracellular matrix deposition, and MMPs activity could be modulated differentially by the AngII receptors. We investigated the role of the AT2R on the capacity of resistance arteries to remodel in response to chronic changes in local blood flow. We investigated flow-mediated remodeling in resistance arteries in PD123319 (AT2R blocker)-treated rats and in AT2R-knockout mice. Second order mesenteric arteries were ligated in vivo, generating low flow (LF) and high flow (HF) arteries, compared to normal flow (NF) vessels. In these vessels a biochemical (protein expression and mRNA level) and a structural study (lumen diameter, intima media thickness and media cross-sectional area) will be performed in order to determine the mechanism involved in the remodeling. After 2 weeks, outward hypertrophic remodeling occurred in HF arteries (increased diameter and medial cross-sectional area) in NaCl treated-rats or wild type mice. Nevertheless, high blood flow-induced remodeling in mesenteric resistance arteries failed to occur in PD123319-treated-rats and in AT2R-KO mice. Inward eutrophic remodeling, which occurred in LF arteries, was not affected to the absence of the AT2R or its blockade. Thus, the diameter enlargement due to a chronic rise in blood flow in resistance arteries involves the AT2R, suggesting a vasodilator and trophic effect of the receptor in arteriolar remodeling in vivo.