α1 -Adrenergic receptors mediate combined signals initiated by mechanical stretch stress and norepinephrine leading to accelerated mouse vein graft atherosclerosis

Objective The molecular mechanism underlying how hypertension with increased norepinephrine (NE) accelerates vascular remodeling is unknown. The present study examined the hypothesis that the additive effects of mechanical stretch stress (SS) and NE on vascular remodeling are mediated by α1 -adrenergic receptors (α1 -ARs). Methods In vitro quiescent mouse vascular smooth muscle cells were cultivated on a flexible membrane and treated by mechanical SS (10% elongation) with or without NE (10−7 mol/L) in the absence or presence of prazosin, a selective antagonist of α1 -ARs (Praz; 10−7 mol/L). In vivo mouse vena cava segments were grafted into carotid arteries, the mice were treated by prazosin (1 mg/kg/d, intraperitoneally) or saline for 2 weeks and 4 weeks, and wall thickness of the vein grafts was quantified. Results Mechanical SS could induce Gαq translocation; increase expression of α1B -ARs, α1D -ARs, and Ki67; and rapidly activate extracellular signal-regulated kinases (ERKs) compared with negative controls ( P < .05). However, the peak levels of ERK activation and Ki67 expression in vascular smooth muscle cells were stimulated by combining SS and NE (ratio of phosphorylated ERK [pERK]/β-actin and Ki67 positive rates, SS+NE [1.07 ± 0.04 and 73% ± 3%]; SS [0.83 ± 0.07 and 53% ± 2%]; NE [0.63 ± 0.11 and 42% ± 2%]), which could be partially inhibited by prazosin (ratio of pERK/β-actin and Ki67 positive rates, SS+NE+Praz [0.83 ± 0.08 and 40% ± 7% vs SS+NE; P < .05], SS+Praz [0.60 ± 0.04 and 26% ± 2% vs SS; P < .05], NE+Praz [0.32 ± 0.12 and 23% ± 2% vs NE; P