FUNDC1-dependent mitochondria-associated endoplasmic reticulum membranes are involved in angiogenesis and neoangiogenesis

• Published in: Nature communications 2021-05, Vol.12 (1), p.2616-13, Article 2616
• Main Authors: Wang, Cheng, Dai, Xiaoyan, Wu, Shengnan, Xu, Wenjing, Song, Ping, Huang, Kai, Zou, Ming-Hui
• Format: Article
• Language: English
• Subjects: 13/1; 13/95; 14/34; 147/137; 38/15; 49/88; 631/80/642/1463; 631/80/642/333; 692/4019/592/16; 692/4028/67/2328; 82/80; Angiogenesis; Animals; Blood vessels; Calcium; Calcium - metabolism; Calcium ions; Clonal deletion; Cytoplasm - metabolism; Cytosol; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum - ultrastructure; Endothelial cells; Endothelial Cells - metabolism; Gene Silencing; Human Umbilical Vein Endothelial Cells; Humanities and Social Sciences; Humans; Intracellular Membranes - drug effects; Intracellular Membranes - metabolism; Membrane proteins; Membrane Proteins - genetics; Membrane Proteins - metabolism; Membranes; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Electron, Transmission; Mitochondria; Mitochondria - metabolism; Mitochondria - ultrastructure; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; multidisciplinary; Neovascularization, Pathologic - genetics; Neovascularization, Physiologic - drug effects; Neovascularization, Physiologic - genetics; Phosphorylation; Proteins; Retina - metabolism; RNA, Small Interfering; Science; Science (multidisciplinary); Serum response factor; Serum Response Factor - metabolism; Vascular endothelial growth factor; Vascular Endothelial Growth Factor Receptor-2 - metabolism; Vascular Endothelial Growth Factor Receptor-2 - pharmacology; Xenograft Model Antitumor Assays
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-22771-3

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 Ca 2+ 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. Mitochondria-associated ER membranes (MAMs) are involved in the regulation of many cellular functions. Here, the authors report that FUNDC1-dependent mitochondria-associated endoplasmic reticulum membranes play an essential role in the process of angiogenesis and neoangiogenesis.