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1 Department of Surgery, Division of Pediatric Surgery, Medical College of Wisconsin, Milwaukee, WI, USA; the Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, USA
2 Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA
3 Department of Surgery, Division of Pediatric Surgery, Medical College of Wisconsin, Milwaukee, WI, USA
4 Department of Surgery, Division of Pediatric Surgery, Medical College of Wisconsin, Milwaukee, WI, USA; the Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, USA; the Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, USA
5 Department of Surgery, Division of Pediatric Surgery, Medical College of Wisconsin, Milwaukee, WI, USA; Free Radical Research Center, Medical College of Wisconsin, Milwaukee, WI, USA
* To whom correspondence should be addressed. E-mail: kpritch{at}mcw.edu.
An increase in the association of heat shock protein 90 (hsp90) with endothelial nitric oxide synthase (eNOS) is well-recognized for increasing nitric oxide (.NO) production. In spite of the progress in this field, the mechanisms by which hsp90 modulates eNOS remain unclear due, in part, to the fact that geldanamycin (GA) redox cycles to generate superoxide anion (O2.-) and the fact inhibiting hsp90 with GA or radicicol (RAD) destabilizes tyrosine kinases that rely on the chaperone for maturation. In this report, we determine the extent to which these side effects alter vascular and endothelial cell function in physiologically relevant systems and in cultured endothelial cells. VEGF-stimulated vascular permeability, as measured by Evans Blue leakage in the ears of male Swiss mice in vivo and acetylcholine (ACh)-induced vasodilation of isolated, pressurized mandibular arterioles from male C57BL6 mice ex vivo were attenuated by L
-nitroargininemethylester (L-NAME), geldanamycin (GA) and radicicol (RAD). DETA NONOate, a slow releasing .NO donor, increased vasodilation of arterioles pretreated with GA, RAD and L-NAME equally well, except at 10-5 M, the highest concentration used, where vasodilation was greater in pressurized arterioles treated with L-NAME than in arterioles pretreated with GA or RAD alone. Both GA and RAD reduced .NO release from stimulated endothelial cell cultures and increased O2.- production in the endothelium of isolated aortas, by an L-NAME-inhibitable mechanism. Pretreatment with RAD increased stimulated O2.- production from eNOS, whereas pretreatment with genistein (GE), a broad-spectrum tyrosine kinase inhibitor, did not; however, pretreatment with GE+RAD resulted in a super-induced state of uncoupled eNOS activity upon stimulation. These data suggest that the tyrosine kinases, either directly or indirectly, and hsp90-dependent signaling pathways act in concert to suppress
uncoupled eNOS activity.
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