SUMOylation of VEGFR2 regulates its intracellular trafficking and pathological angiogenesis

• Published in: Nature communications Vol. 9; no. 1; pp. 3303 - 16
• Main Authors: Zhou, Huanjiao Jenny, Xu, Zhe, Wang, Zongren, Zhang, Haifeng, Zhuang, Zhen W., Simons, Michael, Min, Wang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.08.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13/109; 13/95; 38/23; 45/23; 45/70; 45/77; 631/337/458/538; 631/443/592/16; 631/80/2023/2022; 96/100; 96/2; 96/31; Acetylation; Angiogenesis; Animals; Clonal deletion; Cornea; Cornea - blood supply; Cysteine Endopeptidases - metabolism; Diabetes; Diabetes mellitus; Diabetes Mellitus - pathology; Endopeptidases; Endopeptidases - metabolism; Endothelial cells; Gene Deletion; Gene Knock-In Techniques; Gene Silencing; Golgi apparatus; Golgi Apparatus - drug effects; Golgi Apparatus - metabolism; Human Umbilical Vein Endothelial Cells - drug effects; Human Umbilical Vein Endothelial Cells - metabolism; Humanities and Social Sciences; Humans; Intracellular Space - metabolism; Ischemia; Lysine; Male; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; Neovascularization, Pathologic - metabolism; Post-translation; Protein Transport; Retina; Retina - pathology; Science; Science (multidisciplinary); Signal Transduction - drug effects; Signaling; SUMO protein; SUMO-1 Protein - metabolism; Sumoylation; Therapeutic applications; Ubiquitination; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - pharmacology; Vascular Endothelial Growth Factor Receptor-2 - chemistry; Vascular Endothelial Growth Factor Receptor-2 - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-05812-2

Regulation of VEGFR2 represents an important mechanism for the control of angiogenesis. VEGFR2 activity can be regulated by post-translational modifications such as ubiquitination and acetylation. However, whether VEGFR2 can be regulated by SUMOylation has not been investigated. Here we show that endothelial-specific deletion of the SUMO endopeptidase SENP1 reduces pathological angiogenesis and tissue repair during hindlimb ischemia, and VEGF-induced angiogenesis in the cornea, retina, and ear. SENP1-deficient endothelial cells show increased SUMOylation of VEGFR2 and impaired VEGFR2 signalling. SUMOylation at lysine 1270 retains VEGFR2 in the Golgi and reduces its surface expression, attenuating VEGFR2-dependent signalling. Moreover, we find that SENP1 is downregulated and VEGFR2 hyper-SUMOylated in diabetic settings and that expression of a non-SUMOylated form of VEGFR2 rescues angiogenic defects in diabetic mice. These results show that VEGFR2 is regulated by deSUMOylation during pathological angiogenesis, and propose SENP1 as a potential therapeutic target for the treatment of diabetes-associated angiogenesis. VEGFR2 is a central regulator of angiogenesis. Here Zhou et al. report that SUMOylation of VEGFR2 regulates its subcellular localisation and activity, and that endothelial-specific knockout of the SUMO endopeptidase SENP1 protects against VEGFR2-mediated pathological angiogenesis.