Enhanced voluntary alcohol consumption after estrogen supplementation negates estrogen-mediated vascular repair in ovariectomized mice.
Preclinical and observational studies in ovariectomized (OVX) animals and pre- and postmenopausal women, respectively, have suggested the cardioprotective effects of estrogen replacement therapy. However, randomized clinical trials have not confirmed estrogen-mediated cardioprotection. Although uncertainties about the duration and optimal type of estrogen replacement regimen might explain the disparity, other factors that may mask the protective effects of 17beta-estradiol (E2) on cardiovascular outcome need scrutiny. Increased ethanol consumption may be one such factor. We examined the effect of E2 supplementation on ethanol consumption in OVX mice and the effect of ethanol consumption on E2-mediated vascular repair, in vivo. OVX mice implanted with E2 pellets consumed significantly more ethanol, compared with those receiving placebo pellets. E2-induced increase in ethanol consumption was not affected by the absence of either estrogen receptor-alpha or -beta. Reendothelialization after carotid artery denudation was repressed, and neovascularization in ischemic hind limbs was blunted in mice consuming ethanol, despite E2 supplementation. In vitro, ethanol dose-dependently attenuated E2-induced endothelial cell (EC) proliferation and tube formation activity and enhanced EC apoptosis, suggesting that ethanol blocks E2-induced EC survival and function. Taken together our data suggest that increased ethanol consumption after E2 supplementation blunts the beneficial effects of E2 on EC function and that novel approaches to estrogen replacement for cardioprotection may benefit from the control of alcohol consumption.
Rajasingh
Johnson
J
Division of Cardiovascular Research, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02135, USA.
Bord
Evelyn
E
Qin
Gangjian
G
Ii
Masaaki
M
Silver
Marcy
M
Hamada
Hiromichi
H
Ahluwalia
Deepali
D
Goukassian
David
D
Zhu
Yan
Y
Losordo
Douglas W
DW
Kishore
Raj
R
D000428:Alcohol Drinking / Q000503:physiopathology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D020212:Carotid Artery Injuries / Q000503:physiopathology* / Q000601:surgery; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D004958:Estradiol / Q000494:pharmacology*; D015914:Estrogen Replacement Therapy; D005260:Female; D006614:Hindlimb / Q000098:blood supply; D007511:Ischemia / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology; D010052:Ovariectomy; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D014836:Volition / Q000187:drug effects / Q000502:physiology
D004958:Estradiol