The mitogenic effect of 17beta-estradiol on in vitro endothelial cell proliferation and on in vivo reendothelialization are both dependent on vascular endothelial growth factor.
In addition to their actions on reproductive function, estrogens have important effects on endothelial cells. The present study was designed to evaluate the mechanism(s) by which 17beta-estradiol (E2) promotes endothelial cell proliferation. The potential involvement of vascular endothelial growth factor (VEGF) was investigated by the coadministration of polyclonal anti-VEGF antibody. First, the effect of E2 on the proliferation of cultured foetal bovine aortic endothelial cells (FBAEC) was studied. E2 stimulated this proliferation with an EC50 between 10(-11) and 10(-10) M and this effect was inhibited by the anti-VEGF antibody. The effect of a physiological dose of E2 was then studied in the rat model of carotid injury. After deendothelializing balloon injury, reendothelialization of the denuded surface may influence the growth of the underlying smooth muscle cells. Male Sprague-Dawley rats were castrated and then received E2 from subcutaneously implanted pellets that released 3.2 microg/kg/day. Endothelial regrowth (Evans blue staining) and neointimal thickening were evaluated 2 weeks after the carotid injury. In comparison to the placebo group, E2 increased the extent of reendothelialization (p = 0.0002) and reduced neointimal thickening (p = 0.0007). Anti-VEGF antibody abolished the effect of E2 on reendothelialization as well as on neointimal thickening. Thoracic aorta VEGF content was increased in E2-treated rats compared to control rats. In conclusion, the present study demonstrates that E2 increases endothelial cell proliferation in vitro and reendothelialization in vivo by means of a mechanism dependent on endogenous VEGF. This effect could contribute to the antiatherogenic effect of a physiological dose of E2.
Concina
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P
INSERM U397, U466, Laboratoire de Physiologie et Service de Chirurgie Expérimentale, CHU Rangueil, et Laboratoire de Biologie Moléculaire Eucaryote, CNRS UPR 9006, Université Paul-Sabatier, Toulouse, France.
Sordello
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S
Barbacanne
M A
MA
Elhage
R
R
Pieraggi
M T
MT
Fournial
G
G
Plouet
J
J
Bayard
F
F
Arnal
J F
JF
D000818:Animals; D001013:Aorta, Thoracic / Q000196:embryology / Q000293:injuries / Q000473:pathology / Q000503:physiopathology; D002404:Catheterization / Q000009:adverse effects; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D016228:Endothelial Growth Factors / Q000096:biosynthesis / Q000502:physiology*; D004730:Endothelium, Vascular / Q000196:embryology / Q000293:injuries / Q000473:pathology* / Q000503:physiopathology*; D004958:Estradiol / Q000494:pharmacology*; D005333:Fetus; D008222:Lymphokines / Q000096:biosynthesis / Q000502:physiology*; D008297:Male; D008934:Mitogens / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014945:Wound Healing / Q000502:physiology*
D016228:Endothelial Growth Factors; D008222:Lymphokines; D008934:Mitogens; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D004958:Estradiol