Published online before print February 17, 2005, doi: 10.1161/01.RES.0000159936.38601.22
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© 2005 American Heart Association, Inc.
Integrative Physiology |
A Role for Endoglin in Coupling eNOS Activity and Regulating Vascular Tone Revealed in Hereditary Hemorrhagic Telangiectasia
From the Cancer Research Program (M.T., S.V., M.L.), Hospital for Sick Children, Toronto; Heart and Stroke Richard Lewar Center of Excellence (M.T., R.G., M.H., M.L.), University of Toronto; Division of Cellular & Molecular Biology (R.G., M.G.K., M.H.), Toronto General Hospital Research Institute, Toronto; and Meakins-Christie Laboratories (K.G., D.H.E.), Department of Medicine, McGill University, Montreal, Canada.
Correspondence to Dr Michelle Letarte, Cancer Research Program, Hospital for Sick Children, 555 University Ave, Toronto, Ontario, M5G1X8, Canada. E-mail mablab{at}sickkids.ca
Decreased endothelial NO synthase (eNOS)-derived NO bioavailability and impaired vasomotor control are crucial factors in cardiovascular disease pathogenesis. Hereditary hemorrhagic telangiectasia type 1 (HHT1) is a vascular disorder associated with ENDOGLIN (ENG) haploinsufficiency and characterized by venous dilatations, focal loss of capillaries, and arteriovenous malformations (AVMs). We report that resistance arteries from Eng+/– mice display an eNOS-dependent enhancement in endothelium-dependent dilatation and impairment in the myogenic response, despite reduced eNOS levels. We have found that eNOS is significantly reduced in endoglin-deficient endothelial cells because of decreased eNOS protein half-life. We demonstrate that endoglin can reside in caveolae and associate with eNOS, suggesting a stabilizing function of endoglin for eNOS. After Ca2+-induced activation, endoglin-deficient endothelial cells have reduced eNOS/Hsp90 association, produce less NO, and generate more eNOS-derived superoxide (O2–), indicating that endoglin also facilitates eNOS/Hsp90 interactions and is an important regulator in the coupling of eNOS activity. Treatment with an O2– scavenger reverses the vasomotor abnormalities in Eng+/– arteries, suggesting that uncoupled eNOS and resulting impaired myogenic response represent early events in HHT1 pathogenesis and that the use of antioxidants may provide a novel therapeutic modality.
Key Words: endothelium • superoxide • vascular disease • vascular tone • vasodilatation
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