Bone marrow-derived mononuclear cells (BMMNCs) enhance postischemic neovascularization, and their therapeutic use is currently under clinical investigation. However, cardiovascular risk factors, including diabetes mellitus and hypercholesterolemia, lead to the abrogation of BMMNCs proangiogenic potential. NO has been shown to be critical for the proangiogenic function of BMMNCs, and increased endothelial NO synthase (eNOS) activity promotes vessel growth in ischemic conditions. We therefore hypothesized that eNOS overexpression could restore both the impaired neovascularization response and decreased proangiogenic function of BMMNCs in clinically relevant models of diabetes and hypercholesterolemia. Transgenic eNOS overexpression in diabetic, atherosclerotic, and wild-type mice induced a 1.5- to 2.3-fold increase in postischemic neovascularization compared with control. eNOS overexpression in diabetic or atherosclerotic BMMNCs restored their reduced proangiogenic potential in ischemic hind limb. This effect was associated with an increase in BMMNC ability to differentiate into cells with endothelial phenotype in vitro and in vivo and an increase in BMMNCs paracrine function, including vascular endothelial growth factor A release and NO-dependent vasodilation. Moreover, although wild-type BMMNCs treatment resulted in significant progression of atherosclerotic plaque in ischemic mice, eNOS transgenic atherosclerotic BMMNCs treatment even had antiatherogenic effects. Cell-based eNOS gene therapy has both proangiogenic and antiatherogenic effects and should be further investigated for the development of efficient therapeutic neovascularization designed to treat ischemic cardiovascular disease.

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Keywords angiogenesis, angiogenic gene therapy, animal cell, animal experiment, animal model, article, atherosclerosis, atherosclerotic plaque, bone marrow cell, bone marrow derived mononuclear cell, bone marrow transplantation, cell differentiation, cell function, cell therapy, cholesterol, cholesterol blood level, controlled study, diabetes mellitus, disease course, endothelial nitric oxide synthase, endothelium, femoral artery, gastrocnemius muscle, heart muscle ischemia, hindlimb, hypercholesterolemia, immunohistochemistry, ischemia, macrophage, mononuclear cell, mouse, n(g) nitroarginine methyl ester, neovascularization (pathology), nitric oxide, nonhuman, nonviral gene therapy, paracrine signaling, phenotype, priority journal, protein blood level, protein expression, protein secretion, reactive oxygen metabolite, vasculotropin A, vasodilatation, wild type
Persistent URL dx.doi.org/10.1016/j.ajpath.2010.11.043, hdl.handle.net/1765/23740
Citation
Mees, B.M.E, Récalde, A, Loinard, C, Tempel, D, Godinho, M.F, Vilar, J, … de Crom, M.P.G. (2011). Endothelial nitric oxide synthase overexpression restores the efficiency of bone marrow mononuclear cell-based therapy. American Journal of Pathology, 178(1), 55–60. doi:10.1016/j.ajpath.2010.11.043