Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/103244
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dc.contributor.authorKikuchi, R.-
dc.contributor.authorNakamura, K.-
dc.contributor.authorMacLauchlan, S.-
dc.contributor.authorNgo, D.-
dc.contributor.authorShimizu, I.-
dc.contributor.authorFuster, J.-
dc.contributor.authorKatanasaka, Y.-
dc.contributor.authorYoshida, S.-
dc.contributor.authorQiu, Y.-
dc.contributor.authorYamaguchi, T.-
dc.contributor.authorMatsushita, T.-
dc.contributor.authorMurohara, T.-
dc.contributor.authorGokce, N.-
dc.contributor.authorBates, D.-
dc.contributor.authorHamburg, N.-
dc.contributor.authorWalsh, K.-
dc.date.issued2014-
dc.identifier.citationNature Medicine, 2014; 20(12):1464-1471-
dc.identifier.issn1078-8956-
dc.identifier.issn1546-170X-
dc.identifier.urihttp://hdl.handle.net/2440/103244-
dc.description.abstractPeripheral 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.-
dc.description.statementofresponsibilityRyosuke 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-
dc.language.isoen-
dc.publisherNature Publishing Group-
dc.rights© 2014 Nature America, Inc. All rights reserved.-
dc.source.urihttp://dx.doi.org/10.1038/nm.3703-
dc.subjectPeriphery artery disease-
dc.titleAn antiangiogenic isoform of VEGF-A contributes to impaired vascularization in peripheral artery disease-
dc.typeJournal article-
dc.identifier.doi10.1038/nm.3703-
pubs.publication-statusPublished-
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