Endothelial ARHGEF26 is an angiogenic factor promoting VEGF signalling.

Autor:	Zhu QM; Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, 75 Ames Street, Cambridge, MA 02142, USA.; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA., MacDonald BT; Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, 75 Ames Street, Cambridge, MA 02142, USA., Mizoguchi T; Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, 75 Ames Street, Cambridge, MA 02142, USA.; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA., Chaffin M; Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, 75 Ames Street, Cambridge, MA 02142, USA., Leed A; Center for the Development of Therapeutics, The Broad Institute of Harvard and MIT, Cambridge, MA, USA., Arduini A; Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, 75 Ames Street, Cambridge, MA 02142, USA., Malolepsza E; Genomics Platform, The Broad Institute of Harvard and MIT, Cambridge, MA, USA., Lage K; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA., Kaushik VK; Center for the Development of Therapeutics, The Broad Institute of Harvard and MIT, Cambridge, MA, USA., Kathiresan S; Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, 75 Ames Street, Cambridge, MA 02142, USA.; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Verve Therapeutics, Cambridge, MA, USA., Ellinor PT; Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, 75 Ames Street, Cambridge, MA 02142, USA.; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
Jazyk:	angličtina
Zdroj:	Cardiovascular research [Cardiovasc Res] 2022 Oct 21; Vol. 118 (13), pp. 2833-2846.
DOI:	10.1093/cvr/cvab344
Abstrakt:	Aims: Genetic studies have implicated the ARHGEF26 locus in the risk of coronary artery disease (CAD). However, the causal pathways by which DNA variants at the ARHGEF26 locus confer risk for CAD are incompletely understood. We sought to elucidate the mechanism responsible for the enhanced risk of CAD associated with the ARHGEF26 locus. Methods and Results: In a conditional analysis of the ARHGEF26 locus, we show that the sentinel CAD-risk signal is significantly associated with various non-lipid vascular phenotypes. In human endothelial cell (EC), ARHGEF26 promotes the angiogenic capacity, and interacts with known angiogenic factors and pathways. Quantitative mass spectrometry showed that one CAD-risk coding variant, rs12493885 (p.Val29Leu), resulted in a gain-of-function ARHGEF26 that enhances proangiogenic signalling and displays enhanced interactions with several proteins partially related to the angiogenic pathway. ARHGEF26 is required for endothelial angiogenesis by promoting macropinocytosis of Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) on cell membrane and is crucial to Vascular Endothelial Growth Factor (VEGF)-dependent murine vessel sprouting ex vivo. In vivo, global or tissue-specific deletion of ARHGEF26 in EC, but not in vascular smooth muscle cells, significantly reduced atherosclerosis in mice, with enhanced plaque stability. Conclusions: Our results demonstrate that ARHGEF26 is involved in angiogenesis signaling, and that DNA variants within ARHGEF26 that are associated with CAD risk could affect angiogenic processes by potentiating VEGF-dependent angiogenesis. Competing Interests: Conflict of interest: P.E. has received sponsored research support from Bayer AG and IBM Health. He has also served on advisory boards or consulted for Bayer AG, Quest Diagnostics, MyoKardia and Novartis. T.M. and S.K. are employees of Verve Therapeutics. S.K. holds equity in Verve Therapeutics, Maze Therapeutics, Catabasis, and San Therapeutics. He is a member of the scientific advisory boards for Regeneron Genetics Center and Corvidia Therapeutics; he has served as a consultant for Acceleron, Eli Lilly, Novartis, Merck, Novo Nordisk, Novo Ventures, Ionis, Alnylam, Aegerion, Haug Partners, Noble Insights, Leerink Partners, Bayer Healthcare, Illumina, Colour Genomics, MedGenome, Quest, and Medscape; he reports patents related to a method of identifying and treating a person having a predisposition to or afflicted with cardiometabolic disease (20180010185) and a genetics risk predictor (20190017119). (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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