A role for endoglin in coupling eNOS activity and regulating vascular tone revealed in hereditary hemorrhagic telangiectasia.
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.
Toporsian
Mourad
M
Cancer Research Program, Hospital for Sick Children, Toronto, Ontario, Canada.
Gros
Robert
R
Kabir
Mohammed G
MG
Vera
Sonia
S
Govindaraju
Karuthapillai
K
Eidelman
David H
DH
Husain
Mansoor
M
Letarte
Michelle
M
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D015703:Antigens, CD; D001794:Blood Pressure / Q000187:drug effects; D051242:Caveolin 1; D022461:Caveolins / Q000032:analysis; D002478:Cells, Cultured / Q000187:drug effects; D015536:Down-Regulation; D000071063:Endoglin; D004730:Endothelium, Vascular / Q000502:physiology; D004789:Enzyme Activation / Q000502:physiology; D018841:HSP90 Heat-Shock Proteins / Q000032:analysis / Q000502:physiology; D006579:Heterozygote; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008099:Liver / Q000201:enzymology; D021962:Membrane Microdomains / Q000737:chemistry / Q000201:enzymology; D008638:Mesenteric Arteries / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000502:physiology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000032:analysis / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D009599:Nitroprusside / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D011956:Receptors, Cell Surface; D015398:Signal Transduction / Q000502:physiology; D013482:Superoxide Dismutase / Q000494:pharmacology; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000201:enzymology / Q000235:genetics; D014471:Umbilical Veins / Q000166:cytology; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000502:physiology; D014655:Vascular Resistance / Q000235:genetics / Q000502:physiology*; D014664:Vasodilation / Q000187:drug effects
D015703:Antigens, CD; D051242:Caveolin 1; D022461:Caveolins; C064206:ENG protein, human; D000071063:Endoglin; C502004:Eng protein, mouse; D018841:HSP90 Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011956:Receptors, Cell Surface; D019010:Vascular Cell Adhesion Molecule-1; D009599:Nitroprusside; D010656:Phenylephrine; D009569:Nitric Oxide; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D013482:Superoxide Dismutase; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester