Differential Roles of AT ₁ and AT ₂ Receptor Subtypes in Vascular Trophic and Phenotypic Changes in Response to Stimulation With Angiotensin II

Abstract

The aim of this study was to investigate the roles of angiotensin II (Ang II) receptor subtypes 1 (AT1) and 2 (AT2) in producing vascular wall hypertrophy and qualitative changes in smooth muscle cell gene expression. Wistar rats were treated for 23 days with osmotic minipumps containing solvent and either Ang II (120 ng.kg-1.min-1) or PD123319 (30 mg.kg-1.d-1), an AT2 receptor antagonist. In addition, rats receiving solvent and either Ang II or PD123319 were given losartan, an AT1 receptor antagonist, in the drinking water (10 mg.kg-1.d-1). Vascular wall hypertrophy and smooth muscle phenotype were characterized by morphometric analysis combined with immunohistochemistry. Ang II-induced hypertension was associated with the development of medial hypertrophy of the aorta and coronary arteries accompanied by reversion of vascular smooth muscle cells (VSMCs) toward an immature phenotype, as shown by the expression of cellular fibronectin and nonmuscle myosin. Losartan treatment, which restored normal arterial pressure, prevented all these changes. PD123319 treatment, which had no effect on blood pressure, prevented only vascular hypertrophy, with no effect on VSMC phenotype. Administration of only losartan to normal rats reproduced the Ang II-induced vascular hypertrophy, with no effect on VSMC phenotype. Taken together, these results suggest that (1) the trophic effect of Ang II on VSMCs is mediated via AT2 receptor subtypes and (2) changes in VSMC phenotypes are triggered mainly through AT1 receptor subtypes.

Effects of Angiotensin II Type 1 Receptor Antagonist on Smooth Muscle Cell Phenotype in Intramyocardial Arteries from Spontaneously Hypertensive Rats

“…Based on the results of the specific localization of SM1, SM2, and GATA-6 in the intramyocardial arteries, we demonstrated that 20-week-old SHR showed a significant phenotypic change of SMCs in the intramyocardial arteries towards the synthetic type compared with 20-week-old WKY. Our results for the phenotypic change of SMCs in the hearts were similar to those reported previously, since VSMCs have been shown to modulate their state of differentiation in response to the activation of the local reninAng system, and this plays a crucial role in proliferation and vascular remodeling in hypertension (4,5,9). In addition, VSMCs from SHR produce Ang II and express phenotypic change toward the synthetic type more than those from WKY, which are independent of hypertension (18,19).…”

“…First, the different effects on the phenotypic change of VSMCs in the intramyocardial arteries could be related to differences in the direct inhibition of Ang II stimulation through the AT1 receptor by FK-739 and enalapril, because it has been reported that Ang II might play an important role in the SMC phenotype change in SHR, but not WKY (9,13,(18)(19)(20), which is mainly controlled through the AT1 receptors (5,21), and an AT1 receptor antagonist has been shown to inhibit the Ang II-induced migration of coronary artery SMCs (22). In addition, the difference in the amount of stimulation through the Ang II type 2 (AT2) receptor may have contributed to the different results between FK-739 and enalapril (5).…”

Angiotensin II (ATII)-inducible Platelet-derived Growth Factor A-chain Gene Expression Is p42/44 Extracellular Signal-regulated Kinase-1/2 and Egr-1-dependent and Mediated via the ATII Type 1 but Not Type 2 Receptor

“…Inhibitors such as these have been used by other groups to shed light on pathways utilized by ATII in vivo. For example, ATII-induced vascular wall hypertrophy in rats is blocked by both Losartan and PD123319 (72), but while Losartan restored normal arterial pressure, PD123319 had no effect (72). Our demonstration that ATII induction of p42/44 ERK activity, Egr-1, and PDGF-A expression is mediated through the AT1 receptor is supported by observations in vivo.…”

The potential role of angiotensin II in the vasculature

“…Vascular wall hypertrophy was characterised by morphometric analysis combined with either immunohistochemistry or conventional histological staining. Conventional morphometry 43 and image analysis after smooth muscle ␣-actin (SM␣-actin) immunolabelling 44 allowed the evaluation of media thickness in the aorta and coronary arteries respectively. Prolonged Ang II infusion (23 days) induced significant thickening of the media in both aorta and coronary arteries, independent of luminal diameter.…”