| First Author | Kikuchi R | Year | 2014 |
| Journal | Nat Med | Volume | 20 |
| Issue | 12 | Pages | 1464-71 |
| PubMed ID | 25362254 | Mgi Jnum | J:227803 |
| Mgi Id | MGI:5702823 | Doi | 10.1038/nm.3703 |
| Citation | Kikuchi R, et al. (2014) An antiangiogenic isoform of VEGF-A contributes to impaired vascularization in peripheral artery disease. Nat Med 20(12):1464-71 |
| abstractText | 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. |
