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(Circulation Research. 2007;101:1319.)
© 2007 American Heart Association, Inc.

Integrative Physiology

Sex-Dependent Attenuation of Plaque Growth After Treatment With Bone Marrow Mononuclear Cells

Wendy D. Nelson^*, Andrey G. Zenovich^*, Harald C. Ott, Craig Stolen, Gabriel J. Caron, Angela Panoskaltsis-Mortari, Samuel A. Barnes, III, Xiangrong Xin, Doris A. Taylor

From the Center for Cardiovascular Repair (A.G.Z., G.J.C., D.A.T.), Department of Pediatrics (A.P.M.), and the School of Mathematics and Department of Biomedical Engineering (X.X.), University of Minnesota, Minneapolis; R&D Systems (W.D.N.), Minneapolis, Minn; Massachusetts General Hospital (H.C.O.), Boston; Boston Scientific Corporation (G.S.), Natick, Mass; and the School of Nursing (S.A.B.), University of Arkansas, Fayetteville.

Correspondence to Doris A. Taylor, PhD, Medtronic Bakken Professor of Integrative Biology, Physiology and Medicine, Director, Center for Cardiovascular Repair, University of Minnesota, 7-105A Nils Hasselmo Hall, 312 Church St SE, Minneapolis, MN 55455. E-mail dataylor{at}umn.edu

There are clinically relevant differences in symptomatology, risk stratification, and efficacy of therapies between men and women with coronary artery disease. Sex-based differences in plaque attenuation after administration of bone marrow mononuclear cells (BMNCs) are unknown. Forty-five male and 57 female apolipoprotein-E knockout (apoE^–/–) mice were fed a high-fat diet. At 14 weeks of age, animals received 4 biweekly intravenous sex-matched (males, n=11; females, n=13) or -mismatched (males, n=12; females, n=14) BMNCs obtained from C57BL6/J mice. The rest of the apoE^–/– mice were vehicle treated (males, n=13; females, n=20) or were age-matched untreated controls (males, n=9; females, n=10). Aortic plaque burden, progenitor cell profiles in bone marrow (BM) and 22 circulating cytokines/chemokines were examined 1 week following the final injection. Only female BMNCs infused into male apoE^–/– recipients significantly decreased plaque formation (P<0.001). This reparative response univariately correlated with increased CD34⁺ (P=0.02), CD45⁺ (P=0.0001), and AC133⁺/CD34⁺ (P=0.001) cell percentages in the BM of recipients but not with total serum cholesterol or percentage of BM-CD31⁺/CD45^low cells. In a multivariate analysis, BM-AC133⁺/CD34⁺ and BM-CD45⁺ percentage counts correlated with a lower plaque burden (P<0.05). Increased granulocyte colony-stimulating factor levels highly correlated with plaque attenuation (r=–0.86, P=0.0004). In untreated apoE^–/– mice of either sex, BM-AC133⁺/CD34⁺ cells rose initially and then fell as plaque accumulated; however, BM-AC133⁺/CD34⁺ percentages were higher in females at all times (P0.01). We have demonstrated an atheroprotective effect of female-derived BMNCs administered to male atherosclerotic apoE^–/– mice; this reparative response correlated with the upregulation of BM-AC133⁺/CD34⁺ and CD45⁺ cells and of circulating granulocyte colony-stimulating factor. Atherosclerotic female apoE^–/– mice did not exhibit atheroprotection after BMNCs of either sex. Our findings may have implications for clinical cell therapy trials for coronary artery disease. Further exploration of sex-based differences in atheroprotection and vascular repair is warranted.

Key Words: atherosclerosis • bone marrow • cytokines • gender • stem cells