Abstract
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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Acetylcholine / pharmacology
-
Animals
-
Antigens, CD
-
Blood Pressure / drug effects
-
Caveolin 1
-
Caveolins / analysis
-
Cells, Cultured / drug effects
-
Down-Regulation
-
Endoglin
-
Endothelium, Vascular / physiology
-
Enzyme Activation / physiology
-
HSP90 Heat-Shock Proteins / analysis
-
HSP90 Heat-Shock Proteins / physiology
-
Heterozygote
-
Humans
-
Intracellular Signaling Peptides and Proteins / deficiency
-
Intracellular Signaling Peptides and Proteins / genetics
-
Intracellular Signaling Peptides and Proteins / physiology*
-
Liver / enzymology
-
Membrane Microdomains / chemistry
-
Membrane Microdomains / enzymology
-
Mesenteric Arteries / drug effects
-
Mesenteric Arteries / enzymology
-
Mesenteric Arteries / physiology
-
Mice
-
Mice, Inbred C57BL
-
Mice, Knockout
-
Myocytes, Smooth Muscle / physiology
-
NG-Nitroarginine Methyl Ester / pharmacology
-
Nitric Oxide / biosynthesis
-
Nitric Oxide Synthase / analysis
-
Nitric Oxide Synthase / physiology*
-
Nitric Oxide Synthase Type II
-
Nitric Oxide Synthase Type III
-
Nitroprusside / pharmacology
-
Phenylephrine / pharmacology
-
Receptors, Cell Surface
-
Signal Transduction / physiology
-
Superoxide Dismutase / pharmacology
-
Telangiectasia, Hereditary Hemorrhagic / enzymology
-
Telangiectasia, Hereditary Hemorrhagic / genetics
-
Umbilical Veins / cytology
-
Vascular Cell Adhesion Molecule-1 / genetics
-
Vascular Cell Adhesion Molecule-1 / physiology
-
Vascular Resistance / genetics
-
Vascular Resistance / physiology*
-
Vasodilation / drug effects
Substances
-
Antigens, CD
-
Caveolin 1
-
Caveolins
-
ENG protein, human
-
Endoglin
-
Eng protein, mouse
-
HSP90 Heat-Shock Proteins
-
Intracellular Signaling Peptides and Proteins
-
Receptors, Cell Surface
-
Vascular Cell Adhesion Molecule-1
-
Nitroprusside
-
Phenylephrine
-
Nitric Oxide
-
NOS3 protein, human
-
Nitric Oxide Synthase
-
Nitric Oxide Synthase Type II
-
Nitric Oxide Synthase Type III
-
Nos3 protein, mouse
-
Superoxide Dismutase
-
Acetylcholine
-
NG-Nitroarginine Methyl Ester