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  2. Critical role of mitogen-inducible gene 6 in restraining endothelial cell permeability to maintain vascular homeostasis

Critical role of mitogen-inducible gene 6 in restraining endothelial cell permeability to maintain vascular homeostasis

  • J Cell Commun Signal. 2022 Oct 25. doi: 10.1007/s12079-022-00704-z.
Liying Xing 1 Guanqun Huang 1 Rongyuan Chen 1 Lijuan Huang 1 Juanxi Liu 1 Xiangrong Ren 1 Shasha Wang 1 Haiqing Kuang 1 Anil Kumar 1 Jong Kyong Kim 1 Qin Jiang 2 Xuri Li 3 Chunsik Lee 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Sun Yat-sen University, Guangzhou, 510060, China.
  • 2 Affiliated Eye Hospital of Nanjing Medical University, Nanjing, 210000, China. [email protected].
  • 3 State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Sun Yat-sen University, Guangzhou, 510060, China. [email protected].
  • 4 State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Sun Yat-sen University, Guangzhou, 510060, China. [email protected].
Abstract

Although mitogen-inducible gene 6 (MIG6) is highly expressed in vascular endothelial cells, it remains unknown whether MIG6 affects vascular permeability. Here, we show for the first time a critical role of MIG6 in limiting vascular permeability. We unveil that genetic deletion of Mig6 in mice markedly increased VEGFA-induced vascular permeability, and MIG6 knockdown impaired endothelial barrier function. Mechanistically, we reveal that MIG6 inhibits VEGFR2/KDR/Flk-1 phosphorylation by binding to the VEGFR2/KDR/Flk-1 kinase domain 2, and MIG6 knockdown increases the downstream signaling of VEGFR2/KDR/Flk-1 by enhancing phosphorylation of PLCγ1 and eNOS. Moreover, MIG6 knockdown disrupted the balance between RAC1 and RHOA GTPase activation, leading to endothelial cell barrier breakdown and the elevation of vascular permeability. Our findings demonstrate an essential role of MIG6 in maintaining endothelial cell barrier integrity and point to potential therapeutic implications of MIG6 in the treatment of diseases involving vascular permeability. Xing et al. (2022) investigated the critical role of MIG6 in vascular permeability. MIG6 deficiency promotes VEGFA-induced vascular permeability via activation of PLCγ1-Ca2+-eNOS signaling and perturbation of the balance in RAC1/RHOA activation, resulting in endothelial barrier disruption.

Keywords

Endothelial cell barrier; MIG6; VEGFR2; Vascular permeability.

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