title: Endothelial nitric oxide synthase overexpression restores the efficiency of bone marrow mononuclear cell-based therapy.
abstract: 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.
authors.affiliation: Department of Vascular Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Barend
authors.initials: B
authors.lastname: Mees
authors.forename: Alice
authors.initials: A
authors.lastname: Récalde
authors.forename: Céline
authors.initials: C
authors.lastname: Loinard
authors.forename: Dennie
authors.initials: D
authors.lastname: Tempel
authors.forename: Marcia
authors.initials: M
authors.lastname: Godinho
authors.forename: José
authors.initials: J
authors.lastname: Vilar
authors.forename: Rien
authors.initials: R
authors.lastname: van Haperen
authors.forename: Bernard
authors.initials: B
authors.lastname: Lévy
authors.forename: Rini
authors.initials: R
authors.lastname: de Crom
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Silvestre
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000503:physiopathology / Q000628:therapy*; D015316:Genetic Therapy / Q000379:methods*; D006614:Hindlimb / Q000098:blood supply; D006801:Humans; D007511:Ischemia / Q000628:therapy*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009000:Monocytes / Q000201:enzymology* / Q000637:transplantation*; D018919:Neovascularization, Physiologic / Q000235:genetics*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*
chemical_list: D001057:Apolipoproteins E; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III