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Type: Journal article
Title: An antiangiogenic isoform of VEGF-A contributes to impaired vascularization in peripheral artery disease
Author: Kikuchi, R.
Nakamura, K.
MacLauchlan, S.
Ngo, D.
Shimizu, I.
Fuster, J.
Katanasaka, Y.
Yoshida, S.
Qiu, Y.
Yamaguchi, T.
Matsushita, T.
Murohara, T.
Gokce, N.
Bates, D.
Hamburg, N.
Walsh, K.
Citation: Nature Medicine, 2014; 20(12):1464-1471
Publisher: Nature Publishing Group
Issue Date: 2014
ISSN: 1078-8956
Statement of
Ryosuke Kikuchi, Kazuto Nakamura, Susan MacLauchlan, Doan Thi-Minh Ngo, Ippei Shimizu, Jose Javier Fuster, Yasufumi Katanasaka, Sumiko Yoshida, Yan Qiu, Terry P Yamaguchi, Tadashi Matsushita, Toyoaki Murohara, Noyan Gokce, David O Bates, Naomi M Hamburg, Kenneth Walsh
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)¹ ², 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.
Keywords: Periphery artery disease
Rights: © 2014 Nature America, Inc. All rights reserved.
RMID: 0030031288
DOI: 10.1038/nm.3703
Appears in Collections:Medicine publications

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