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

作者：Liu, Shuying; Li, Yuhuang; Zhang, Zhengyu; Xie, Fukang; Xu, Qingbo; Huang, Xi; Huang, Jintao; Li, Chaohong^*

来源：Journal of Vascular Surgery, 2013, 57(6): 1645-U261.

DOI：10.1016/j.jvs.2012.09.061

• SMOOTH-MUSCLE-CELLS
• THERAPEUTIC TARGET
• ANGIOTENSIN-II
• BYPASS GRAFTS
• HYPERTENSION
• PROLIFERATION
• ACTIVATION
• PRESSURE
• MANAGEMENT
• PRAZOSIN

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 alpha(1)-adrenergic receptors (alpha(1)-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 a1-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 G alpha q translocation; increase expression of alpha(1B)-ARs, alpha(1D)-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]/beta-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/beta-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 < .05]) or small interfering RNAs of alpha(1B)-ARs and alpha(1D)-ARs (P < .05 vs siRNA control). Significantly increased wall thickness was seen in the vein grafts (VG2W, 39.20 +/- 3.10 mu m; VG4W, 60.35 +/- 4.94 mu m) compared with control veins (negative controls, 9.90 +/- 0.38 mu m; P < .05). The effect was partially inhibited by prazosin (VGP2W, 26.22 +/- 1.84 mu m, and VGP4W, 42.17 +/- 1.75 mu m vs VG2W and VG4W; P < .05). @@@ Conclusions: These results suggest that alpha(1)-ARs may partially mediate the intracellular signals induced by mechanical SS with or without NE via Gaq protein/ERKs pathway triggering increased proliferation of vascular smooth muscle cells and leading to accelerated neointima formation of vein grafts.

• 出版日期2013-6
• 单位中山大学