Centre National de la Recherche Scientifique Unité Mixte de Recherche 6214, Institut National de la Santé et de la Recherche Médicale U771, Université d'Angers, Angers, France.
Hypertension. 2010 Jan;55(1):109-15. doi: 10.1161/HYPERTENSIONAHA.108.127456. Epub 2009 Nov 30.
Angiotensin II is a potent growth factor involved in arterial wall homeostasis. In resistance arteries, chronic increases in blood flow induce a rise in diameter associated with arterial wall hypertrophy. Nevertheless, the role of angiotensin II in this remodeling is unknown. We investigated the effect of blocking angiotensin II production or receptor activation on flow-induced remodeling of mesenteric resistance arteries. Arteries were ligated in vivo to generate high-flow arteries compared with normal flow (control) vessels located at a distance. Arteries were isolated after 1 week for in vitro analysis. Arterial diameter, media surface, endothelial NO synthase expression, superoxide production, and extracellular signal-regulated kinase 1/2 phosphorylation were higher in high-flow than in control arteries. Angiotensin-converting enzyme inhibition (perindopril) and angiotensin II type 1 receptor blockade (candesartan) prevented arterial wall hypertrophy without affecting diameter enlargement. The nonselective vasodilator hydralazine had no effect on remodeling. Although perindopril and candesartan increased endothelial NO synthase expression in high-flow arteries, hypertrophy remained in rats treated with N(G)-nitro-l-arginine methyl ester and mice lacking endothelial NO synthase. Perindopril and candesartan reduced oxidative stress in high-flow arteries, but superoxide scavenging did not prevent hypertrophy. Both Tempol and the absence of endothelial NO synthase prevented the rise in diameter in high-flow vessels. Extracellular signal-regulated kinase 1/2 activation in high-flow arteries was prevented by perindopril and candesartan and not by hydralazine. Extracellular signal-regulated kinase 1/2 inhibition in vivo (U0126) prevented hypertrophy in high-flow arteries. Thus, a chronic rise in blood flow in resistance arteries induces a diameter enlargement involving NO and superoxide, whereas hypertrophy was associated with extracellular signal-regulated kinase 1/2 activation by angiotensin II.
血管紧张素 II 是一种参与动脉壁内稳态的强效生长因子。在阻力血管中，慢性血流增加会导致直径增大，伴随着动脉壁肥厚。然而，血管紧张素 II 在这种重塑中的作用尚不清楚。我们研究了阻断血管紧张素 II 产生或受体激活对肠系膜阻力血管血流诱导重塑的影响。通过体内结扎动脉，使血管产生高血流，与位于远处的正常血流（对照）血管相比。1 周后，将血管分离进行体外分析。与对照血管相比，高血流血管的直径、中膜表面积、内皮型一氧化氮合酶表达、超氧化物产生和细胞外信号调节激酶 1/2 磷酸化均升高。血管紧张素转换酶抑制剂（培哚普利）和血管紧张素 II 受体 1 型阻断剂（坎地沙坦）可预防动脉壁肥厚，而不影响直径增大。非选择性血管扩张剂肼屈嗪对重塑没有影响。虽然培哚普利和坎地沙坦增加了高血流血管内皮型一氧化氮合酶的表达，但在给予 N(G)-硝基-L-精氨酸甲酯和缺乏内皮型一氧化氮合酶的大鼠中，肥厚仍然存在。培哚普利和坎地沙坦降低了高血流血管的氧化应激，但超氧化物清除并未阻止肥厚。Tempol 和缺乏内皮型一氧化氮合酶均可防止高血流血管直径增大。高血流血管中细胞外信号调节激酶 1/2 的激活被培哚普利和坎地沙坦阻断，而不是被肼屈嗪阻断。在体内抑制细胞外信号调节激酶 1/2（U0126）可防止高血流血管的肥厚。因此，阻力血管中的慢性血流增加会引起直径增大，涉及一氧化氮和超氧化物，而肥厚与血管紧张素 II 引起的细胞外信号调节激酶 1/2 激活有关。
