INSERM U771, Angers, France.
Hypertens Res. 2010 Aug;33(8):857-66. doi: 10.1038/hr.2010.83. Epub 2010 Jun 10.
Blood flow reduction induces inward remodeling of resistance arteries (RAs). This remodeling occurs in ischemic diseases, diabetes and hypertension. Nonetheless, the effect of flow reduction per se, independent of the effect of pressure or metabolic influences, is not well understood in RA. As angiotensin II is involved in the response to flow in RA, we hypothesized that angiotensin II may also be involved in the remodeling induced by a chronic flow reduction. We analyzed the effect of angiotensin I-converting enzyme inhibition (perindopril) and angiotensin II type 1 receptor blockade (candesartan) on inward remodeling induced by blood flow reduction in vivo in rat mesenteric RAs (low flow (LF) arteries). After 1 week, diameter reduction in LF arteries was associated with reduced endothelium-dependent relaxation and lower levels of eNOS expression. Superoxide production and extracellular signal-regulated kinases 1/2 (ERK1/2 phosphorylation were higher in LF than in normal flow arteries. Nevertheless, the absence of eNOS or superoxide level reduction (tempol or apocynin) did not prevent LF remodeling. Perindopril and candesartan prevented inward remodeling in LF arteries. Contractility to angiotensin II was reduced in LF vessels by perindopril, candesartan and the ERK1/2 blocker PD98059. ERK1/2 activation (ratio phospho-ERK/ERK) was higher in LF arteries, and this activation was prevented by perindopril and candesartan. ERK1/2 inhibition in vivo (U0126) prevented LF-induced diameter reduction. Thus, inward remodeling because of blood flow reduction in mesenteric RA depends on unopposed angiotensin II-induced contraction and ERK1/2 activation, independent of superoxide production. These findings might be of importance in the treatment of vascular disorders.
血流减少会引起阻力血管（RAs）的内向重构。这种重构发生在缺血性疾病、糖尿病和高血压中。然而，血流减少本身的影响，独立于压力或代谢影响的影响，在 RA 中还没有被很好地理解。由于血管紧张素 II 参与了 RA 对血流的反应，我们假设血管紧张素 II 也可能参与了由慢性血流减少引起的重构。我们分析了血管紧张素转化酶抑制（培哚普利）和血管紧张素 II 型 1 受体阻断（坎地沙坦）对大鼠肠系膜 RA （低流量（LF）动脉）体内血流减少引起的内向重构的影响。1 周后，LF 动脉的直径减小与内皮依赖性松弛的降低和 eNOS 表达水平的降低有关。超氧化物的产生和细胞外信号调节激酶 1/2（ERK1/2 磷酸化在 LF 比在正常血流动脉中更高。然而，缺乏 eNOS 或超氧化物水平的降低（tempol 或 apocynin）并没有阻止 LF 重构。培哚普利和坎地沙坦预防了 LF 动脉的内向重构。培哚普利、坎地沙坦和 ERK1/2 阻滞剂 PD98059 降低了 LF 血管对血管紧张素 II 的收缩性。LF 动脉中 ERK1/2 的激活（磷酸化 ERK/ERK 的比值）更高，培哚普利和坎地沙坦阻止了这种激活。体内 ERK1/2 抑制（U0126）阻止了 LF 诱导的直径减小。因此，肠系膜 RA 血流减少引起的内向重构依赖于不受抑制的血管紧张素 II 诱导的收缩和 ERK1/2 激活，而与超氧化物的产生无关。这些发现可能对血管疾病的治疗有重要意义。
