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Nat Med. 2014 Dec;20(12):1464-71. doi: 10.1038/nm.3703. Epub 2014 Nov 2.

An antiangiogenic isoform of VEGF-A contributes to impaired vascularization in peripheral artery disease.

Author information

1
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.
2
Molecular Cardiology and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, USA.
3
Clinical Cardiology, Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, USA.
4
Microvascular Research Laboratories, School of Physiology and Pharmacology, University of Bristol, Bristol, UK.
5
Cancer and Developmental Biology Laboratory, National Cancer Institute, National Institutes of Health, Frederick, Maryland, USA.
6
Department of Clinical Laboratory, Nagoya University Hospital, Nagoya, Aichi, Japan.
7
Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
8
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.
9
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.

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.

PMID:
25362254
PMCID:
PMC4257756
DOI:
10.1038/nm.3703
[Indexed for MEDLINE]
Free PMC Article

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