Multimerin-2 is an extracellular matrix glycoprotein and member of the elastin microfibril interface-located (EMILIN) family of proteins. Multimerin-2 is deposited along blood vessels and we previously demonstrated that it regulates the VEGFA/VEGFR2 signaling axis and angiogenesis. However, its role in modulating vascular homeostasis remains largely unexplored. Here we identified Multimerin-2 as a key molecule required to maintain vascular stability. RNAi knockdown of Multimerin-2 in endothelial cells led to cell-cell junctional instability and increased permeability. Mechanistically cell-cell junction dismantlement occurred through the phosphorylation of VEGFR2 at Tyr951, activation of Src and phosphorylation of VE-cadherin. To provide an in vivo validation for these in vitro effects, we generated Multimerin-2-/- (Mmrn2-/-) mice. Although Mmrn2-/- mice developed normally and displayed no gross abnormalities, endothelial cells displayed cell junctional defects associated with increased levels of VEGFR2 phospho-Tyr949 (the murine counterpart of human Tyr951), impaired pericyte recruitment and increased vascular leakage. Of note, tumor associated vessels were defective in Mmrn2-/- mice, with increased number of small and often collapsed vessels, concurrent with a significant depletion of pericytic coverage. Consequently, the Mmrn2-/- vessels were less perfused and leakier, leading to increased tumor hypoxia. Chemotherapy efficacy was markedly impaired in Mmrn2-/- mice and this was associated with poor drug delivery to the tumor xenografts. Collectively, our findings demonstrate that Multimerin-2 is required for proper vessel homeostasis and stabilization, and unveil the possibility to utilize expression levels of this glycoprotein in predicting chemotherapy efficacy.

中文翻译：

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Multimerin-2维持血管稳定性和通透性。

Multimerin-2是一种细胞外基质糖蛋白，是弹性蛋白微纤维界面定位（EMILIN）蛋白家族的成员。Multimerin-2沿血管沉积，我们先前证明其可调节VEGFA / VEGFR2信号轴和血管生成。然而，其在调节血管稳态中的作用仍未得到充分探索。在这里，我们确定Multimerin-2为维持血管稳定性所需的关键分子。内皮细胞中Multimerin-2的RNAi敲低导致细胞间连接不稳定和通透性增加。从机理上讲，细胞间连接的拆除是通过Tyr951处VEGFR2的磷酸化，Src的活化和VE-钙黏着蛋白的磷酸化而发生的。为了提供这些体外作用的体内验证，我们生成了Multimerin-2-/-（Mmrn2-/-）小鼠。尽管Mmrn2-/-小鼠发育正常且未显示任何明显异常，但内皮细胞显示与VEGFR2磷酸Tyr949（人类Tyr951的鼠对应物）水平升高，周细胞募集受损和血管渗漏增加相关的细胞连接缺陷。值得注意的是，Mmrn2-/-小鼠中与肿瘤相关的血管是有缺陷的，小的和经常塌陷的血管数量增加，同时周细胞覆盖率显着减少。因此，Mmrn2-/-血管的灌注和渗漏较少，导致肿瘤缺氧增加。在Mmrn2-/-小鼠中，化学疗法的疗效显着受损，这与药物对肿瘤异种移植物的递送不良有关。总的来说，我们的研究结果表明，Multimerin-2是适当的血管稳态和稳定所必需的，