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FUNDC1-dependent mitochondria-associated endoplasmic reticulum membranes are involved in angiogenesis and neoangiogenesis
Nature Communications ( IF 14.7 ) Pub Date : 2021-05-10 , DOI: 10.1038/s41467-021-22771-3
Cheng Wang 1 , Xiaoyan Dai 1 , Shengnan Wu 1 , Wenjing Xu 2 , Ping Song 1 , Kai Huang 2 , Ming-Hui Zou 1
Affiliation  

FUN14 domain-containing protein 1 (FUNDC1) is an integral mitochondrial outer-membrane protein, and mediates the formation of mitochondria-associated endoplasmic reticulum membranes (MAMs). This study aims to determine the contributions of FUNDC1-mediated MAMs to angiogenesis in vitro and in vivo. In cultured endothelial cells, VEGF significantly increases the formation of MAMs and MAM-related proteins, including FUNDC1. Endothelial cell-specific deletion of FUNDC1, which disrupts MAM formation in endothelial cells, lowers VEGFR2 expression and reduces tube formation, spheroid-sprouting, and functional blood vessel formation in vitro and in vivo. Conversely, increased MAM formation using MAM linkers mimics the effects of VEGF and promotes endothelial angiogenesis. Mechanistically, increased MAMs formation led to increased levels of Ca2+ in cytosol, promoted the phosphorylation of serum response factor (SRF) and enhanced the binding of SRF to VEGFR2 promoter, resulting in increased VEGFR2 production, with consequent angiogenesis. Moreover, blocking FUNDC1-related MAM formation with a cell-penetrating inhibitory peptide significantly suppresses the expressions of downstream angiogenic genes and inhibits tumor angiogenesis. We conclude that decreased MAMs formation by silencing FUNDC1 can inhibit angiogenesis by decreasing VEGFR2 expression, and targeting FUNDC1-dependent MAMs might be a promising approach for treating human disorders characterized by defective angiogenesis.



中文翻译:


FUNDC1依赖性线粒体相关内质网膜参与血管生成和新血管生成



含 FUN14 结构域的蛋白 1 (FUNDC1) 是一种完整的线粒体外膜蛋白,介导线粒体相关内质网膜 (MAM) 的形成。本研究旨在确定 FUNDC1 介导的 MAM 对体外和体内血管生成的贡献。在培养的内皮细胞中,VEGF 显着增加 MAM 和 MAM 相关蛋白(包括 FUNDC1)的形成。内皮细胞特异性删除 FUNDC1,会破坏内皮细胞中 MAM 的形成,降低 VEGFR2 表达,并减少体外和体内的管形成、球状体萌芽和功能性血管形成。相反,使用 MAM 连接体增加 MAM 形成可模拟 VEGF 的作用并促进内皮血管生成。从机制上讲,MAM形成增加导致细胞质中Ca 2+水平增加,促进血清反应因子(SRF)的磷酸化并增强SRF与VEGFR2启动子的结合,导致VEGFR2产生增加,从而导致血管生成。此外,用细胞穿透抑制肽阻断FUNDC1相关的MAM形成可显着抑制下游血管生成基因的表达并抑制肿瘤血管生成。我们的结论是,通过沉默 FUNDC1 来减少 MAM 形成,可以通过降低 VEGFR2 表达来抑制血管生成,而靶向 FUNDC1 依赖性 MAM 可能是治疗以血管生成缺陷为特征的人类疾病的一种有前景的方法。

更新日期:2021-05-10
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