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(Circulation Research. 2005;96:684.)
© 2005 American Heart Association, Inc.

Integrative Physiology

A Role for Endoglin in Coupling eNOS Activity and Regulating Vascular Tone Revealed in Hereditary Hemorrhagic Telangiectasia

Mourad Toporsian, Robert Gros, Mohammed G. Kabir, Sonia Vera, Karuthapillai Govindaraju, David H. Eidelman, Mansoor Husain, Michelle Letarte

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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