武汉云克隆科技股份有限公司

Abstract:

Midkine is a pleiotropic factor, which is involved in angiogenesis. However, its mode of action in this process is still ill defined. The function of midkine in arteriogenesis, the growth of natural bypasses from pre-existing collateral arteries, compensating for the loss of an occluded artery has never been investigated. Arteriogenesis is an inflammatory process, which relies on the proliferation of endothelial cells and smooth muscle cells. We show that midkine deficiency strikingly interferes with the proliferation of endothelial cells in arteriogenesis, thereby interfering with the process of collateral artery growth. We identified midkine to be responsible for increased plasma levels of vascular endothelial growth factor A (VEGFA), necessary and sufficient to promote endothelial cell proliferation in growing collaterals. Mechanistically, we demonstrate that leukocyte domiciled midkine mediates increased plasma levels of VEGFA relevant for upregulation of endothelial nitric oxide synthase 1 and 3, necessary for proper endothelial cell proliferation, and that non-leukocyte domiciled midkine additionally improves vasodilation. The data provided on the role of midkine in endothelial proliferation are likely to be relevant for both, the process of arteriogenesis and angiogenesis. Moreover, our data might help to estimate the therapeutic effect of clinically applied VEGFA in patients with vascular occlusive diseases.

摘要：

肝素结合细胞因子是参与血管生成的多向性因子，然而我们尚未明确在此过程中它如何发挥作用。肝素结合细胞因子对动脉生成的作用尚未被研究，如天然侧支从已有侧支动脉生成，改善动脉闭塞。动脉生成是一个依赖于内皮细胞和平滑肌细胞增殖的炎症过程。我们发现血管生成过程中钾缺乏症对内皮细胞增殖产生强烈干扰作用，从而干扰侧支动脉的生长。我们发现肝素结合细胞因子是导致血浆中血管内皮生长因子A(VEGFA)水平升高的原因之一，也是促进血管内皮细胞增殖的必要和充分条件。数据表明，白细胞结合的肝素结合细胞因子使与内皮型一氧化氮合酶1和3表达相关的VEGFA水平升高，促进内皮细胞增殖；而非白细胞结合肝素结合细胞因子能改善血管扩张。相关数据表明肝素结合细胞因子在内皮细胞增殖中作用可能与动脉生成和血管生成有关。此外，我们的研究数据可将有助于评估临床应用VEGFA治疗血管闭塞性疾病的疗效。

使用试剂原文信息：The VEGFA plasma level was measured with a standardized ELISA Kit (R&D Systems, Minneapolis, MN) following the manufacturer's protocol. The ready-SET-go Midkine ELISA-Kit (USCN Life Science Inc., Wuhan, China) was used to measure the MK plasma level following the manufacturer's protocol.