Kikuchi, RyosukeNakamura, KazutoMacLauchlan, SusanNgo, Doan Thi-MinhShimizu, IppeiFuster, Jose JavierKatanasaka, YasufumiYoshida, SumikoQiu, YanYamaguchi, Terry PMatsushita, TadashiMurohara, ToyoakiGokce, NoyanBates, David OHamburg, Naomi MWalsh, Kenneth2024-02-052024-02-052014-12Nat Med. 2014 Dec;20(12):1464-71http://hdl.handle.net/20.500.12105/17482Peripheral 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.engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/Adaptor Proteins, Signal TransducingAnimalsCollateral CirculationDisease Models, AnimalHumansAttribution-NonCommercial-NoDerivatives 4.0 Internacional253622542012146410.1038/nm.37031546-170XNature medicineopen access