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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:997.)
© 2008 American Heart Association, Inc.

Clinical and Population Studies

Gender Differences in Endothelial Progenitor Cells and Cardiovascular Risk Profile

The Role of Female Estrogens

Gian Paolo Fadini; Saula de Kreutzenberg; Mattia Albiero; Anna Coracina; Elisa Pagnin; Ilenia Baesso; Andrea Cignarella; Chiara Bolego; Mario Plebani; Giovanni B. Nardelli; Saverio Sartore; Carlo Agostini; Angelo Avogaro

From Clinical and Experimental Medicine (G.P.F., S.d.K., A.C., E.P., A.A.), Metabolic Division; Biomedical Sciences (M.A., S.S.); Clinical and Experimental Medicine (I.B., C.A.), Clinical Immunology and Hematology; Pharmacology and Anesthesiology (A.C.); Laboratory Medicine (M.P.); Gynecological Science and Human Reproduction (G.B.N.), the University of Padova Medical School; and Pharmacological Sciences (C.B.P, University of Milan, Italy.

Correspondence to Gian Paolo Fadini, MD, Dipartimento di Medicina Clinica e Sperimentale, Malattie del Metabolismo, Policlinico Universitario – v. Giustiniani, 2, 35100 Padova, Italy. E-mail gianpaolofadini{at}hotmail.com

Objective— Endothelial progenitor cells (EPCs) participate in vascular homeostasis and angiogenesis. The aim of the present study was to explore EPC number and function in relation to cardiovascular risk, gender, and reproductive state.

Methods and Results— As measured by flow-cytometry in 210 healthy subjects, CD34⁺KDR⁺ EPCs were higher in fertile women than in men, but were not different between postmenopausal women and age-matched men. These gender gradients mirrored differences in cardiovascular profile, carotid intima-media thickness, and brachial artery flow-mediated dilation. Moreover, EPCs and soluble c-kit ligand varied in phase with menstrual cycle in ovulatory women, suggesting cyclic bone marrow mobilization. Experimentally, hysterectomy in rats was followed by an increase in circulating EPCs. EPCs cultured from female healthy donors were more clonogenic and adherent than male EPCs. Treatment with 17β-estradiol stimulated EPC proliferation and adhesion, via estrogen receptors. Finally, we show that the proangiogenic potential of female EPCs was higher than that of male EPCs in vivo.

Conclusions— EPCs are mobilized cyclically in fertile women, likely to provide a pool of cells for endometrial homeostasis. The resulting higher EPC levels in women than in men reflect the cardiovascular profile and could represent one mechanism of protection in the fertile female population.

We provide evidence that fertile women have a larger pool of circulating endothelial progenitors than men. This may be attributed to the cyclic bone marrow mobilization during menstrual cycle. Thanks to estrogens, female EPCs also display better function and higher vasculogenic properties than male EPCs.

Key Words: gender • endothelium • cardiovascular risk • stem cells • cord blood

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