Journal
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 30, Issue 5, Pages 992-U235Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.110.203935
Keywords
mesenteric artery; myogenic tone; endothelial nitric oxide synthase; raloxifene; selective estrogen receptor modulator
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Funding
- RGC Earmarked [CUHK 4362/04M, 465308]
- CUHK Focused Investment Scheme
- CUHK Li Ka Shing Institute of Health Sciences
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Objective-Selective estrogen receptor modulators (SERMs) inhibit constriction of mammalian conduit arteries. However, it is unknown whether SERMs at therapeutically achievable concentrations could reduce vascular tone in resistance arteries. The present study aimed to examine roles of Ca2+ influx in endothelium and endothelial nitric oxide synthase (eNOS) activation in dilatations induced by raloxifene, a second-generation SERM in myogenically active arteries. Methods and Results-Small mesenteric arteries from Sprague-Dawley rats were isolated and mounted in a pressure myograph for measurement of changes in vessel diameter. [Ca2+](i) images on native endothelial cells of intact arteries were determined by the fluorescence imaging technique, and phosphorylation of eNOS was assayed by Western blotting. Raloxifene (0.3 to 10 nmol/L) produced dilatations on established steady myogenic constriction. Female rat arteries dilated significantly more in response to raloxifene than male arteries. Raloxifene-induced dilatations of female arteries were blunted by N-G-nitro-L-arginine methyl ester but unaffected by 1400W, charybdotoxin plus apamin, wortmannin, or LY294002. Raloxifene (3 nmol/L) triggered rises in endothelial cell [Ca2+](i) and increased eNOS phosphorylation at Ser1177. Both effects were greater in arteries from female rats than in arteries from male rats. Increases in endothelial cell [Ca2+](i) and in eNOS phosphorylation were prevented by removal of extracellular Ca2+ ions. Finally, ICI 182,780 did not affect the raloxifene-stimulated rise in endothelial cell [Ca2+](i), eNOS phosphorylation, and vasodilatations. Chronic raloxifene treatment reduced myogenic constriction in arteries from female but not male rats. Conclusion-Raloxifene at therapeutically relevant concentrations inhibits myogenic constriction by an NO-dependent mechanism that causally involves the elevated [Ca2+](i) in endothelial cells and subsequent eNOS activation. Raloxifene dilates resistance arteries more effectively in female rats, indicating its significant gender-related action on endothelial cells in microcirculation. (Arterioscler Thromb Vasc Biol. 2010;30:992-999.)
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