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

作者：Kikuchi Ryosuke; Nakamura Kazuto; MacLauchlan Susan; Doan Thi Minh Ngo; Shimizu Ippei; Fuster Jose Javier; Katanasaka Yasufumi; Yoshida Sumiko; Qiu Yan; Yamaguchi Terry P; Matsushita Tadashi; Murohara Toyoaki; Gokce Noyan; Bates David O; Hamburg Naomi M; Walsh Kenneth^*

来源：Nature Medicine, 2014, 20(12): 1464-1471.

DOI：10.1038/nm.3703

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 levels of an antiangiogenic VEGF-A splice isoform (VEGF-A(165)b) and a corresponding reduction in levels of the proangiogenic VEGF-A(165)a splice isoform. In mice, VEGF-A(165)b 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-A(165)b 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.

• 出版日期2014-12
• 单位NIH