title: Wnt1 is a proangiogenic molecule, enhances human endothelial progenitor function, and increases blood flow to ischemic limbs in a HGF-dependent manner.
abstract: Human endothelial progenitor cells (hEPCs) participate in neovascularization of ischemic tissues. Function and number of hEPCs decline in patients with cardiovascular disease, and therapeutic strategies to enhance hEPC function remain an important field of investigation. The Wnt signaling system, comprising 19 lipophilic proteins, regulates vascular patterning in the developing embryo. However, the effects of Wnts on hEPCs and the adult vasculature remain unclear. We demonstrate here that Wnt1 is expressed in a subset of endothelial cells lining the murine embryonic dorsal aorta and is reactivated in malignant angiosarcoma, suggesting a strong association of Wnt1 with angiogenesis. We investigate the effects of Wnt1 in enhancing hEPC function and blood flow to ischemic tissues and show that Wnt1 enhances the proliferative and angiogenic functions of hEPCs in a hepatocyte growth factor (HGF)-dependent manner. Injection of Wnt1-expressing hEPCs increases blood flow and capillary density in murine ischemic hindlimbs. Furthermore, injection of Wnt1 protein alone similarly increases blood flow and capillary density in ischemic hindlimbs, and this effect is associated with increased HGF expression in ischemic muscle. These findings demonstrate that Wnt1, a marker of neural crest cells and hitherto unknown angiogenic function, is a novel angiogenic protein that is expressed in developing endothelial cells, exerts salutary effects on postnatal hEPCs, and can be therapeutically deployed to increase blood flow and angiogenesis in ischemic tissues.
authors.affiliation: Department of Medicine, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Costin M
authors.initials: CM
authors.lastname: Gherghe
authors.forename: Jinzhu
authors.initials: J
authors.lastname: Duan
authors.forename: Jucheng
authors.initials: J
authors.lastname: Gong
authors.forename: Mauricio
authors.initials: M
authors.lastname: Rojas
authors.forename: Nancy
authors.initials: N
authors.lastname: Klauber-Demore
authors.forename: Mark
authors.initials: M
authors.lastname: Majesky
authors.forename: Arjun
authors.initials: A
authors.lastname: Deb
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000196:embryology; D004195:Disease Models, Animal; D004622:Embryo, Mammalian / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology* / Q000502:physiology; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism*; D006614:Hindlimb / Q000098:blood supply; D006801:Humans; D007511:Ischemia / Q000209:etiology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000098:blood supply; D018919:Neovascularization, Physiologic / Q000502:physiology*; D058729:Peripheral Arterial Disease / Q000150:complications / Q000628:therapy; D013234:Stem Cells / Q000502:physiology*; D051155:Wnt1 Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D051155:Wnt1 Protein; D017228:Hepatocyte Growth Factor