An antiangiogenic isoform of VEGF-A contributes to impaired vascularization in peripheral artery disease.
An antiangiogenic isoform of VEGF-A contributes to impaired vascularization in peripheral artery disease.
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作者：
外周动脉疾病（PAD）通过动脉闭塞和侧支血管形成不足产生组织缺血。尽管血管内皮生长因子A（血管生成的关键调节因子）的循环水平较高，但PAD中的血管功能不全仍会发生。在此，我们发现临床PAD与抗血管生成VEGF-A剪接亚型（VEGF-A165 b）升高和促血管生成VEGF-A165 a亚型相应减少相关。在PAD的小鼠模型中，VEGF-A165 b在与受损肢体血管重建相关的条件下上调，包括瘦素缺乏症、饮食诱导的肥胖、分泌型卷曲相关蛋白5（Sfrp 5）脂肪因子的基因消除和骨髓细胞中Wnt 5a的转基因过表达。在PAD模型中，VEGF-A165 b的递送抑制缺血性后肢的血运重建，而用同种型特异性中和抗体的治疗逆转了由代谢功能障碍或Wnt 5a/Sfrp 5调节系统中的扰动引起的受损的血运重建表型。这些结果表明，炎症驱动的抗血管生成VEGF-A同种型的表达可有助于缺血性心血管疾病中的受损的侧支化。
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 anti-angiogenic VEGF-A splice isoform (VEGF-A165b), and a corresponding reduction of the pro-angiogenic VEGF-A165a isoform. In a murine model of PAD, VEGF-A165b 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-A165b 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.
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DOI：
10.1161/atvbaha.111.230441
发表时间：
2011-11
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Duscha BD;Robbins JL;Jones WS;Kraus WE;Lye RJ;Sanders JM;Allen JD;Regensteiner JG;Hiatt WR;Annex BH
通讯作者：
Annex BH
影响因子：
6
作者：
Makin, AJ;Chung, NAY;Lip, GYH
通讯作者：
Lip, GYH
影响因子：
12.4
作者：
Mäkinen, K;Manninen, H;Ylä-Herttuala, S
通讯作者：
Ylä-Herttuala, S
分子机制和血管生成的临床应用。
影响因子：
64.8
作者：
Carmeliet, Peter;Jain, Rakesh K.
通讯作者：
Jain, Rakesh K.
影响因子：
64.8
作者：
Stefater, James A., III;Lewkowich, Ian;Rao, Sujata;Mariggi, Giovanni;Carpenter, April C.;Burr, Adam R.;Fan, Jieqing;Ajima, Rieko;Molkentin, Jeffery D.;Williams, Bart O.;Wills-Karp, Marsha;Pollard, Jeffrey W.;Yamaguchi, Terry;Ferrara, Napoleone;Gerhardt, Holger;Lang, Richard A.
通讯作者：
Lang, Richard A.