Hirao Akiko, Kondo Kazunao, Takeuchi Kazuhiko, Inui Naoki, Umemura Kazuo, Ohashi Kyoichi, Watanabe Hiroshi
Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka 431-3192, Japan.
Cardiovasc Res. 2008 Jul 1;79(1):161-8. doi: 10.1093/cvr/cvn111. Epub 2008 May 2.
Denudation and regeneration of the vascular endothelium are important in the pathogenesis of atherosclerosis. The aim of this study is to clarify the mechanisms of functional alterations in remodelled arteries following endothelial injury.
Non-mechanical endothelial injury was induced by 540-nm light irradiation of rose Bengal in femoral arteries of Wistar rats. Endothelium-dependent vasodilation was assessed by the response to acetylcholine (ACh) 1, 2, and 4 weeks after the injury. In control arteries, ACh-induced relaxation was mainly nitric oxide-dependent at all study time points. In injured arteries, this response was completely restored at 1 week, but was more dependent on KCl-sensitive endothelium-derived hyperpolarizing factor production during the first 2 weeks. Cyclooxygenase (COX) isoforms 1 and 2 were detected in the endothelium of injured arteries, and inhibition of prostanoids production with the non-specific COX inhibitor indomethacin substantially enhanced the ACh-induced vasorelaxation response in injured arteries, but did not affect control arteries. Similar effects were observed with the COX-1 inhibitor SC-560, the COX-2 inhibitor NS-398, the thromboxane (TX) A2/prostaglandin (PG) H2 receptor antagonist SQ29548 and the PGF2alpha receptor antagonist AL-8810. However, the TX synthetase inhibitor OKY-046 had no effect on ACh-induced relaxation in injured arteries.
In remodelled arteries following photochemical endothelial injury, the vasoconstrictive prostanoids PGH2 and PGF2alpha, but not TXA2, contribute to changes in endothelium-dependent vascular response via COX-1- and 2-dependent pathways.
血管内皮的剥脱和再生在动脉粥样硬化的发病机制中具有重要意义。本研究旨在阐明内皮损伤后重塑动脉功能改变的机制。
通过对Wistar大鼠股动脉进行孟加拉玫瑰红540纳米光照射诱导非机械性内皮损伤。在损伤后1、2和4周，通过对乙酰胆碱（ACh）的反应评估内皮依赖性血管舒张功能。在对照动脉中，在所有研究时间点，ACh诱导的舒张主要依赖于一氧化氮。在损伤动脉中，这种反应在1周时完全恢复，但在最初2周内更依赖于KCl敏感的内皮衍生超极化因子的产生。在损伤动脉的内皮中检测到环氧化酶（COX）同工型1和2，用非特异性COX抑制剂吲哚美辛抑制前列腺素生成可显著增强损伤动脉中ACh诱导的血管舒张反应，但对对照动脉无影响。使用COX-1抑制剂SC-560、COX-2抑制剂NS-398、血栓素（TX）A2/前列腺素（PG）H2受体拮抗剂SQ29548和PGF2α受体拮抗剂AL-8810也观察到类似效果。然而，TX合成酶抑制剂OKY-046对损伤动脉中ACh诱导的舒张无影响。
在光化学内皮损伤后的重塑动脉中，血管收缩性前列腺素PGH2和PGF2α而非TXA2通过COX-1和2依赖性途径导致内皮依赖性血管反应的变化。
