An anti-angiogenic isoform of VEGF-A contributes to impaired vascularization in peripheral artery disease

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 anti-angiogenic VEGF-A splice isoform (VEGF-A(165)b), and a corresponding reduction of the pro-angiogenic VEGF-A(165)a isoform. In a murine model of PAD, VEGF-A(165)b 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 PAD models, delivery of VEGF-A(165)b inhibited revascularization of ischemic hind limbs, whereas treatment with an isoform-specific neutralizing antibody reversed the impaired revascularization phenotype caused by metabolic dysfunction or perturbations in the Wnt5a/Sfrp5 regulatory system. These results indicate that inflammation driven expression of the anti-angiogenic VEGF-A isoform can contribute to impaired collateralization in ischemic cardiovascular disease.