title: Sex-dependent attenuation of plaque growth after treatment with bone marrow mononuclear cells.
abstract: 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 (P<or=0.01). 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.
authors.affiliation: University of Minnesota, Minneapolis; R&D Systems, Minneapolis, MN 55455, USA.
authors.forename: Wendy D
authors.initials: WD
authors.lastname: Nelson
authors.forename: Andrey G
authors.initials: AG
authors.lastname: Zenovich
authors.forename: Harald C
authors.initials: HC
authors.lastname: Ott
authors.forename: Craig
authors.initials: C
authors.lastname: Stolen
authors.forename: Gabriel J
authors.initials: GJ
authors.lastname: Caron
authors.forename: Angela
authors.initials: A
authors.lastname: Panoskaltsis-Mortari
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Barnes
authors.forename: Xiangrong
authors.initials: X
authors.lastname: Xin
authors.forename: Doris A
authors.initials: DA
authors.lastname: Taylor
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D016026:Bone Marrow Transplantation; D003324:Coronary Artery Disease / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy*; D005260:Female; D007963:Leukocytes, Mononuclear / Q000637:transplantation*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012727:Sex Characteristics
chemical_list: D001057:Apolipoproteins E