Estrogen stimulates heat shock protein 90 binding to endothelial nitric oxide synthase in human vascular endothelial cells - Effects on calcium sensitivity and NO release

Estradiol (E-2) causes endothelium-dependent vasodilation, mediated, in par t, by enhanced nitric oxide (NO) release. We have previously shown that E-2 -induced activation of endothelial nitric oxide synthase (eNOS) reduces its calcium dependence. This pathway of eNOS activation is unique to a limited number of stimuli, including shear stress, the response to which is herbim ycin-inhibitable. Consistent with this, herbimycin and geldanamycin pretrea tment of human umbilical vein endothelial cells (HUVEC) abrogated E-2-stimu lated NO release and cGMP production, respectively. These benzoquinone ansa mycins are potent inhibitors of Hsp90 function, which has recently been sho wn to play a role in stimulus-dependent eNOS activation. As in response to shear, E-2 induced an Hsp90-eNOS association, peaking at 30 min and complet ely inhibited by the conventional estrogen receptor antagonist ICI 182,780, These findings suggest that Hsp90 plays an important role in the rapid, es trogen receptor-mediated modulation of eNOS activation by estrogen.