Transforming growth factor activity is a key determinant for the effect of estradiol on fatty streak deposit in hypercholesterolemic mice.

Objective-Whereas estradiol prevents fatty streak deposit in immunocompetent apoE(-/-) or LDLr-/- mice, it is totally ineffective in immunodeficient mice, underlining the key role of immunoinflammation in this effect. In the present work, the role of several major pro- and antiinflammatory cytokines involved in the atheromatous process was evaluated in the effect of estradiol on fatty streak constitution. Methods and Results-The preventive effect of estradiol was fully maintained in LDLr-/- mice grafted with bone marrow from either IFN-gamma or interleukin (IL)-12- deficient mice, showing that this beneficial effect was not mediated through a specific decrease in the production of these 2 proinflammatory cytokines. Furthermore, IL-10(-/-) apoE(-/-) mice remained protected by estradiol, excluding a significant contribution of this antiinflammatory cytokine. In contrast, the protective effect of estradiol was (1) associated with enhanced aortic expression of TGF-beta 1 in apoE(-/-) mice during early steps of atherogenesis; (2) abolished and even reversed in apoE(-/-) mice administered with a neutralizing anti-TGF-beta antibody; ( 3) abolished in LDLr-/- mice grafted with bone marrow from Smad3-deficient mice. Conclusions-The status of the TGF-beta pathway crucially determines the antiatherogenic effect of estradiol in hypercholesterolemic mice, whereas neither IFN-gamma, IL-12, nor IL-10 are specifically involved in this protection.