title: An antiangiogenic isoform of VEGF-A contributes to impaired vascularization in peripheral artery disease.
abstract: Peripheral artery disease (PAD) generates tissue ischemia through arterial occlusions and insufficient collateral vessel formation. Vascular insufficiency in PAD occurs despite higher circulating levels of vascular endothelial growth factor A (VEGF-A), a key regulator of angiogenesis. Here we show that clinical PAD is associated with elevated levels of an antiangiogenic VEGF-A splice isoform (VEGF-A165b) and a corresponding reduction in levels of the proangiogenic VEGF-A165a splice isoform. In mice, VEGF-A165b expression was upregulated by conditions associated with impaired limb revascularization, including leptin deficiency, diet-induced obesity, genetic ablation of the secreted frizzled-related protein 5 (Sfrp5) adipokine and transgenic overexpression of Wnt5a in myeloid cells. In a mouse model of PAD, delivery of VEGF-A165b inhibited revascularization of ischemic hind limbs, whereas treatment with an isoform-specific neutralizing antibody reversed impaired revascularization caused by metabolic dysfunction or perturbations in the Wnt5a-Sfrp5 regulatory system. These results indicate that inflammation-driven expression of the antiangiogenic VEGF-A isoform can contribute to impaired collateralization in ischemic cardiovascular disease.
authors.affiliation: 1] Molecular Cardiology and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, USA. [2] Department of Medical Technique, Nagoya University Hospital, Nagoya, Aichi, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Kikuchi
authors.affiliation: Molecular Cardiology and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Molecular Cardiology and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: MacLauchlan
authors.affiliation: Clinical Cardiology, Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Doan Thi-Minh
authors.initials: DT
authors.lastname: Ngo
authors.affiliation: Molecular Cardiology and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Ippei
authors.initials: I
authors.lastname: Shimizu
authors.affiliation: Molecular Cardiology and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Jose Javier
authors.identifier: 000000025970629X
authors.initials: JJ
authors.lastname: Fuster
authors.affiliation: Molecular Cardiology and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Katanasaka
authors.affiliation: Molecular Cardiology and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Sumiko
authors.initials: S
authors.lastname: Yoshida
authors.affiliation: Microvascular Research Laboratories, School of Physiology and Pharmacology, University of Bristol, Bristol, UK.
authors.forename: Yan
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: Cancer and Developmental Biology Laboratory, National Cancer Institute, National Institutes of Health, Frederick, Maryland, USA.
authors.forename: Terry P
authors.initials: TP
authors.lastname: Yamaguchi
authors.affiliation: Department of Clinical Laboratory, Nagoya University Hospital, Nagoya, Aichi, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Matsushita
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
authors.affiliation: Clinical Cardiology, Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Noyan
authors.initials: N
authors.lastname: Gokce
authors.affiliation: 1] Microvascular Research Laboratories, School of Physiology and Pharmacology, University of Bristol, Bristol, UK. [2] Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Queen's Medical Centre, Nottingham, UK.
authors.forename: David O
authors.initials: DO
authors.lastname: Bates
authors.affiliation: 1] Molecular Cardiology and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, USA. [2] Evans Department of Medicine and the Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Naomi M
authors.initials: NM
authors.lastname: Hamburg
authors.affiliation: Molecular Cardiology and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Walsh
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D003097:Collateral Circulation; D004195:Disease Models, Animal; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000502:physiology*; D058729:Peripheral Arterial Disease / Q000378:metabolism*; D020033:Protein Isoforms; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics; D000071818:Wnt-5a Protein; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D036341:Intercellular Signaling Peptides and Proteins; D020033:Protein Isoforms; D042461:Vascular Endothelial Growth Factor A; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C487972:Sfrp5 protein, mouse; D000094742:Secreted Frizzled-Related Proteins; C438615:Wnt5a protein, mouse