HDL-associated estradiol stimulates endothelial NO synthase and vasodilation in an SR-BI-dependent manner.
Cardiovascular diseases remain the leading cause of death in the United States. Two factors associated with a decreased risk of developing cardiovascular disease are elevated HDL levels and sex - specifically, a decreased risk is found in premenopausal women. HDL and estrogen stimulate eNOS and the production of nitric oxide, which has numerous protective effects in the vascular system including vasodilation, antiadhesion, and anti-inflammatory effects. We tested the hypothesis that HDL binds to its receptor, scavenger receptor class B type I (SR-BI), and delivers estrogen to eNOS, thereby stimulating the enzyme. HDL isolated from women stimulated eNOS, whereas HDL isolated from men had minimal activity. Studies with ovariectomized and ovariectomized/estrogen replacement mouse models demonstrated that HDL-associated estradiol stimulation of eNOS is SR-BI dependent. Furthermore, female HDL, but not male HDL, promoted the relaxation of muscle strips isolated from C57BL/6 mice but not SR-BI null mice. Finally, HDL isolated from premenopausal women or postmenopausal women receiving estradiol replacement therapy stimulated eNOS, whereas HDL isolated from postmenopausal women did not stimulate eNOS. We conclude that HDL-associated estrodial is capable of the stimulating eNOS. These studies establish a new paradigm for examining the cardiovascular effects of HDL and estrogen.
Gong
Ming
M
Department of Pediatrics, University of Kentucky Medical School, Lexington, Kentucky, USA.
Wilson
Melinda
M
Kelly
Thomas
T
Su
Wen
W
Dressman
James
J
Kincer
Jeanie
J
Matveev
Sergey V
SV
Guo
Ling
L
Guerin
Theresa
T
Li
Xiang-An
XA
Zhu
Weifei
W
Uittenbogaard
Annette
A
Smart
Eric J
EJ
D000818:Animals; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D005263:Femoral Artery / Q000187:drug effects / Q000502:physiology; D020249:Hormone Replacement Therapy; D006801:Humans; D066298:In Vitro Techniques; D008075:Lipoproteins, HDL / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000187:drug effects / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D010052:Ovariectomy; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D051122:Scavenger Receptors, Class B; D012737:Sex Factors; D014664:Vasodilation / Q000187:drug effects
D018955:CD36 Antigens; D008075:Lipoproteins, HDL; D008565:Membrane Proteins; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; C495124:SCARB1 protein, human; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D004958:Estradiol; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse