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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:2214.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Transforming Growth Factor Activity Is a Key Determinant for the Effect of Estradiol on Fatty Streak Deposit in Hypercholesterolemic Mice

Pierre Gourdy; Alexia Schambourg; Cédric Filipe; Victorine Douin-Echinard; Barbara Garmy-Susini; Bertrand Calippe; François Tercé; Francis Bayard; Jean-François Arnal

From the Institut National de la Santé et de la Recherche Médicale, INSERM U858 (P.G., A.S., C.F., V.D.E., B.G.S., B.C., F.B., J.F.A.), Institut de Médecine Moléculaire de Rangueil, Toulouse, France; Service de Diabétologie (P.G.), Pôle Cardio-Vasculaire et Métabolique, CHU Toulouse Rangueil, France; and INSERM U563 (F.T.), Département Lipoprotéines et Médiateurs Lipidiques, CHU Toulouse Purpan, France.

Correspondence to Pierre Gourdy, INSERM U858, Institut de Médecine Moléculaire de Rangueil, BP 84225, 31432 Toulouse Cedex 4, France. E-mail gourdyp{at}toulouse.inserm.frThe role of several cytokines involved in the atheromatous process was evaluated in the protective effect of estradiol on fatty streak constitution. We demonstrate that the integrity of the TGF-beta pathway is absolutely required for this beneficial property of estradiol, whereas neither IFN-gamma, IL-12 or, IL-10 deficiency altered this effect.

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- 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-β1 in apoE^–/– mice during early steps of atherogenesis; (2) abolished and even reversed in apoE^–/– mice administered with a neutralizing anti–TGF-β antibody; (3) abolished in LDLr^–/– mice grafted with bone marrow from Smad3-deficient mice.

Conclusions— The status of the TGF-β pathway crucially determines the antiatherogenic effect of estradiol in hypercholesterolemic mice, whereas neither IFN-, IL-12, nor IL-10 are specifically involved in this protection.

The role of several cytokines involved in the atheromatous process was evaluated in the protective effect of estradiol on fatty streak constitution. We demonstrate that the integrity of the TGF-beta pathway is absolutely required for this beneficial property of estradiol, whereas neither IFN-gamma, IL-12 or, IL-10 deficiency altered this effect.

Key Words: atherosclerosis • inflammation • cytokine • TGF-β • estrogen

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