Estradiol inhibits leukocyte adhesion and transendothelial migration in rabbits in vivo - Possible mechanisms for gender differences in atherosclerosis

The mechanism by which estrogens protect against atherosclerosis is not kno wn. We evaluated in vivo whether there is a gender difference in monocyte a dhesion and subendothelial migration in hypercholesterolemic rabbits and wh ether any gender differences observed are due to estradiol. Monocyte adhesi on and subendothelial migration were assessed in a blinded fashion by analy zing a standardized segment of aorta using a scanning electron microscope. We also assessed whether estradiol modulates induction of vascular cell adh esion molecule-1 (VCAM-1) protein using Western blot and flow cytometric an alyses. We observed that male rabbits develop more monocyte adhesion and su bendothelial migration than do female rabbits during hypercholesterolemia. We also observed that oophorectomized rabbits given physiological estradiol supplementation demonstrate fewer adherent and subendothelial monocytes th an do oophorectomized rabbits given placebo. VCAM-1 protein expression was increased in aortae obtained from hypercholesterolemic, oophorectomized ani mals supplemented with placebo, and this increase was attenuated by estradi ol. Finally, in cultured rabbit aortic endothelial cells stimulated with ly sophosphatidylcholine, we observed an increase in VCAM-1 protein that was i nhibited in a concentration-dependent fashion by estradiol. We have demonst rated in vivo that there is a gender difference in monocyte adhesion to end othelial cells and transendothelial migration after hypercholesterolemia an d that this gender difference is due in part to estradiol. Our results also suggest that estradiol inhibits monocyte adhesion by inhibiting expression of VCAM-1.