DYNAMIC ACTIVATION OF ENDOTHELIAL NITRIC-OXIDE SYNTHASE BY HSP90

Heat-shock protein 90 (Hsp90) coordinates the trafficking and regulati on of diverse signalling proteins, but its precise role in regulating specific cellular targets is not known(1,2). Here we show that Hsp90 a ssociates with endothelial nitric oxide synthase (eNOS) and is rapidly recruited to the eNOS complex by agonists that stimulate production o f nitric oxide, namely vascular endothelial growth factor, histamine a nd fluid shear stress. Moreover, the binding of Hsp90 to eNOS enhances the activation of eNOS. Inhibition of signalling through Hsp90 attenu ates both agonist-stimulated production of nitric oxide and endotheliu m-dependent relaxation of isolated blood vessels. Our results indicate that Hsp90 facilitates signalling mediated by growth-factor, G-protei n and mechanotransduction pathways that lead to the activation of eNOS . These observations indicate that in addition to its role as a molecu lar chaperone involved in protein folding and maturation, Hsp90 may al so be recruited to cellular targets depending on the activation state of the cell.