Increased endothelial exocytosis and generation of endothelin-1 contributes to constriction of aged arteries.
Increased endothelial exocytosis and generation of endothelin-1 contributes to constriction of aged arteries.
复制标题
DOI：
10.1161/circresaha.109.210229
复制
发表时间：
2010-07-23
影响因子：
20.1
通讯作者：
Flavahan NA
中科院分区：
文献类型：
--
作者：
Goel A;Su B;Flavahan S;Lowenstein CJ;Berkowitz DE;Flavahan NA
Circulating levels of endothelin-1 (ET-1) and endogenous ETA-mediated constriction are increased in human aging. The mechanisms responsible are not known. Investigate the storage, release and activity of ET-1 system in arteries from young and aged Fischer-344 rats. After NO synthase inhibition (L-NAME), thrombin contracted aged arteries, which was inhibited by endothelial-denudation, ETA-receptor antagonism (BQ123), ECE inhibition (phosphoramidon, SM19712) or by inhibiting exocytosis (TAT-NSF,N-ethylmaleimide-sensitive-factor inhibitor). Thrombin did not cause endothelium-dependent contraction of young arteries. In aged but not young arteries, thrombin rapidly increased ET-1 release, which was abolished by endothelium-denudation or TAT-NSF. L-NAME did not affect ET-1 release. ET-1 immunofluorescent staining was punctate and distinct from Von Willebrand factor (VWF). VWF and ET-1 immunofluorescent intensity was similar in young and aged quiescent arteries. Thrombin rapidly increased ET-1 staining and decreased VWF staining in aged but had no effect in young aortas. After L-NAME, thrombin decreased VWF staining in young aortas. NO donor DEA-NONOate (1–100nmol/L) reversed thrombin-induced exocytosis in young (VWF) but not aged L-NAME-treated aortas (VWF,ET-1). Expression of preproET-1 mRNA and ECE-1 mRNA were increased in aged compared to young endothelium. BigET-1 levels and contraction to exogenous BigET-1 (but not ET-1) were also increased in aged compared to young arteries. The stimulated exocytotic release of ET-1 is dramatically increased in aged endothelium. This reflects increased reactivity of exocytosis, increased expression and storage of ET-1 precursor peptides, and increased expression of ECE-1. Altered endothelial exocytosis of ET-1 and other mediators may contribute to cardiovascular pathology in aging.
