Changes in Vsmc Phenotypes in Ang Ii-Dependent Hypertension of TGR (mREN2) 27 (Tgr) Transgenic Rats
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 (ETA). 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 ETA/ETB antagonist Bosentan (100 mg/Kg, Group B) the Ang II AT-1 specific receptor antagonist Irbesartan (50 mg/Kg BW, Group I) or the ETA 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, ETA, 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<0.001) lower systolic BP (161±8 mmHg, vs 269±23 Group P; vs 254±21 Group BMS), LV weight (2.28±0.15 mg/g BW vs 3.71±0.26, 3.38±0.27 and 3.96±0.51), and normalized media thickness of the mesenteric arterioles (22.3±0.6 μm vs 25.3±0.5, 25.5±0.7 and 24.1±1.5). Hypertension, LVH and medial arterioles hypertrophy in group P TGR were paralleled by a shift of VSMC toward a fetal phenotype in the iliac artery, despite no change in the expression of both irET-1 and ETA. The VSMC phenotypic shift was prevented by both irbesartan and Bosentan, but not by the ETA-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 ETB- but not ETA-mediated mechanisms.