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oai:repisalud.isciii.es:20.500.12105/174822024-05-27T19:25:12Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605

00925njm 22002777a 4500 dc Kikuchi, Ryosuke author Nakamura, Kazuto author MacLauchlan, Susan author Ngo, Doan Thi-Minh author Shimizu, Ippei author Fuster, Jose Javier author Katanasaka, Yasufumi author Yoshida, Sumiko author Qiu, Yan author Yamaguchi, Terry P author Matsushita, Tadashi author Murohara, Toyoaki author Gokce, Noyan author Bates, David O author Hamburg, Naomi M author Walsh, Kenneth author 2014-12 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. Nat Med. 2014 Dec;20(12):1464-71 10.1038/nm.3703 1546-170X Nature medicine 25362254 http://hdl.handle.net/20.500.12105/17482 An antiangiogenic isoform of VEGF-A contributes to impaired vascularization in peripheral artery disease.