Changes in Vsmc Phenotypes in Ang Ii-Dependent Hypertension of TGR (mREN2) 27 (Tgr) Transgenic Rats

Abstract

57 Arterial hypertension is associated with vascular smooth muscle cells (VSMC) phenotypic differentiation, but the role of Ang II and ET-1 is still unclear. Thus, we investigated the changes of VSMC phenotypes in Ang II-dependent hypertension and the role of ET-1 and its A receptor (ET A ). Four-week old heterozygote male TGR rats (n=24) were body weight (BW)- and blood pressure (BP)-matched and randomly allocated to receive orally a placebo (Group P), the mixed ET A /ET B antagonist Bosentan (100 mg/Kg, Group B) the Ang II AT-1 specific receptor antagonist Irbesartan (50 mg/Kg BW, Group I) or the ET A selective antagonist BMS-182874 (52 mg/Kg BW, Group BMS). After 4-wk of treatments, during which BW and BP were measured weekly, animals were euthanized; the iliac artery and mesenteric arterioles were collected. In the latter the structural changes were assessed with a myograph. Immunohistochemistry with a panel of different antibodies specific for ET-1, ET A , smooth muscle (SM) myosin, SM actin, SM 22, myosin heavy chains Apla 22 and fibronectin EIIIA was carried out. The fetal, neonatal and adult aorta from normotensive Sprague-Dawley rats were studied as control. Compared to all other groups, Group I rats showed significantly (p A . The VSMC phenotypic shift was prevented by both irbesartan and Bosentan, but not by the ET A -selective antagonist BM 182874. Thus, Ang II-dependent hypertension of TGR is associated with both vascular hypertrophy and a shift of VSMC toward a fetal phenotype, which occurs through AT-1- and ET B - but not ET A -mediated mechanisms.