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Nat Commun. 2018 Aug 17;9(1):3303. doi: 10.1038/s41467-018-05812-2.

SUMOylation of VEGFR2 regulates its intracellular trafficking and pathological angiogenesis.

Author information

1
Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, 10 Amistad St., New Haven, CT, 06520, USA. huanjiao.zhou@yale.edu.
2
Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, 10 Amistad St., New Haven, CT, 06520, USA.
3
Department of Ophthalmology, First Affiliated Hospital of Jinan University, Guangzhou, 510630, Guangdong Province, P. R. China.
4
The First Affiliated Hospital, Sun Yat-sen University, Zhongshan Road II, Guangzhou, 510080, P. R. China.
5
Section of Cardiology, Department of Internal Medicine, Yale University School of Medicine, 10 Amistad St., New Haven, CT, 06520, USA.
6
Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, 10 Amistad St., New Haven, CT, 06520, USA. wang.min@yale.edu.
7
The First Affiliated Hospital, Sun Yat-sen University, Zhongshan Road II, Guangzhou, 510080, P. R. China. wang.min@yale.edu.

Abstract

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.

PMID:
30120232
PMCID:
PMC6098000
DOI:
10.1038/s41467-018-05812-2
[Indexed for MEDLINE]
Free PMC Article

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