title: Fibroblast growth factor 9 delivery during angiogenesis produces durable, vasoresponsive microvessels wrapped by smooth muscle cells.
abstract: The therapeutic potential of angiogenic growth factors has not been realized. This may be because formation of endothelial sprouts is not followed by their muscularization into vasoreactive arteries. Using microarray expression analysis, we discovered that fibroblast growth factor 9 (FGF9) was highly upregulated as human vascular smooth muscle cells (SMCs) assemble into layered cords. FGF9 was not angiogenic when mixed with tissue implants or delivered to the ischemic mouse hind limb, but instead orchestrated wrapping of SMCs around neovessels. SMC wrapping in implants was driven by sonic hedgehog-mediated upregulation of PDGFRβ. Computed tomography microangiography and intravital microscopy revealed that microvessels formed in the presence of FGF9 had enhanced capacity to receive flow and were vasoreactive. Moreover, the vessels persisted beyond 1 year, remodeling into multilayered arteries paired with peripheral nerves. This mature physiological competency was attained by targeting mesenchymal cells rather than endothelial cells, a finding that could inform strategies for therapeutic angiogenesis and tissue engineering.
authors.affiliation: Robarts Research Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Canada.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Frontini
authors.forename: Zengxuan
authors.initials: Z
authors.lastname: Nong
authors.forename: Robert
authors.initials: R
authors.lastname: Gros
authors.forename: Maria
authors.initials: M
authors.lastname: Drangova
authors.forename: Caroline
authors.initials: C
authors.lastname: O'Neil
authors.forename: Mona N
authors.initials: MN
authors.lastname: Rahman
authors.forename: Oula
authors.initials: O
authors.lastname: Akawi
authors.forename: Hao
authors.initials: H
authors.lastname: Yin
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Ellis
authors.forename: J Geoffrey
authors.initials: JG
authors.lastname: Pickering
mesh_terms: D000595:Amino Acid Sequence; D042501:Angiogenic Proteins / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D051525:Fibroblast Growth Factor 9 / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000637:transplantation*; D006614:Hindlimb / Q000098:blood supply*; D006801:Humans; D007511:Ischemia / Q000628:therapy; D017078:Laser-Doppler Flowmetry; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D046228:Microarray Analysis; D055806:Microvessels / Q000378:metabolism; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000637:transplantation; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000637:transplantation*; D018919:Neovascularization, Physiologic
chemical_list: D042501:Angiogenic Proteins; D051525:Fibroblast Growth Factor 9