Bell L, Madri J A
Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, CT 06510.
Am J Pathol. 1990 Jul;137(1):7-12.
The blood vessel wall's response to injury is an important determinant of luminal size and vessel function. The physiologic migration of endothelial cells from the edges of a wound and the pathophysiologic migration of medial smooth muscle cells into the intima are two important components of the vessel wall's response to injury. The influence of the angiotensin system on endothelial and smooth muscle cell migration have not been examined. In the present study, the influence of angiotensin system components on bovine aortic endothelial cell (BAEC) and bovine aortic smooth muscle cell (BASMC) migration after release of cultured cell monolayers from contact inhibition was determined. The angiotensin-converting enzyme (ACE) inhibitor lisinopril increased BAEC migration 41% +/- 3% (P less than 0.001), as did the specific angiotensin II antagonist sar1, ile8-angiotensin II (SAR) (41% +/- 3% (P less than 0.001). Exogenous angiotensin I and angiotensin II did not affect BAEC migration. Exogenous angiotensin II abolished the effect of lisinopril on BAEC migration. Lisinopril increased cell-associated u-plasminogen activator (u-PA) 23% +/- 3% (P less than 0.001) in migrating BAEC and angiotensin II abolished this increase. SAR increased u-PA 33% +/- 0% (P less than 0.001). In contrast, these agents had the opposite effect on smooth muscle cells. Angiotensin II increased smooth muscle cell migration 40% +/- 3% (P less than 0.001), and this effect was abolished by SAR. Angiotensin II also increased cell-associated u-PA 83% +/- 7% (P less than 0.001) in migrating BASMC. The increase in BAEC migration with inhibition of endothelial cell angiotensin II stimulation, either with lisinopril or SAR, also was associated with an increase in cell-associated u-PA. These results indicate that lisinopril interrupts an autocrine pathway in endothelial cells, in which endothelial cell-derived angiotensin I is converted to angiotensin II by ACE, and imply that angiotensin-converting enzyme inhibitors in vivo would act to reduce vessel wall injury by directly increasing the rate of endothelial cell wound closure; by increasing the antithrombotic tendency of the endothelium via enhanced u-PA; and indirectly, by decreasing production of angiotensin II and thereby the rate of smooth muscle cell migration into the intima.
血管壁对损伤的反应是管腔大小和血管功能的重要决定因素。内皮细胞从伤口边缘的生理性迁移以及中膜平滑肌细胞向内膜的病理性迁移是血管壁对损伤反应的两个重要组成部分。血管紧张素系统对内皮细胞和平滑肌细胞迁移的影响尚未得到研究。在本研究中，测定了血管紧张素系统成分对培养的细胞单层解除接触抑制后牛主动脉内皮细胞（BAEC）和牛主动脉平滑肌细胞（BASMC）迁移的影响。血管紧张素转换酶（ACE）抑制剂赖诺普利使BAEC迁移增加41%±3%（P<0.001），特异性血管紧张素II拮抗剂sar1、ile8-血管紧张素II（SAR）也有同样作用（41%±3%（P<0.001））。外源性血管紧张素I和血管紧张素II不影响BAEC迁移。外源性血管紧张素II消除了赖诺普利对BAEC迁移的作用。赖诺普利使迁移的BAEC中细胞相关尿纤溶酶原激活剂（u-PA）增加23%±3%（P<0.001），血管紧张素II消除了这种增加。SAR使u-PA增加33%±0%（P<0.001）。相反，这些药物对平滑肌细胞有相反的作用。血管紧张素II使平滑肌细胞迁移增加40%±3%（P<0.001），这种作用被SAR消除。血管紧张素II还使迁移的BASMC中细胞相关u-PA增加83%±7%（P<0.001）。用赖诺普利或SAR抑制内皮细胞血管紧张素II刺激导致的BAEC迁移增加也与细胞相关u-PA增加有关。这些结果表明，赖诺普利中断了内皮细胞中的自分泌途径，在内皮细胞中，内皮细胞衍生的血管紧张素I被ACE转化为血管紧张素II，并提示体内血管紧张素转换酶抑制剂将通过直接提高内皮细胞伤口闭合率来减少血管壁损伤；通过增强u-PA增加内皮的抗血栓倾向；以及间接通过减少血管紧张素II的产生，从而降低平滑肌细胞向内膜迁移的速率。
