Endothelial ARHGEF26 is an angiogenic factor promoting VEGF signalling . Issue 13 (26th November 2021)

• Record Type: Journal Article
• Authors: Zhu, Qiuyu Martin; MacDonald, Bryan T; Mizoguchi, Taiji; Chaffin, Mark; Leed, Alison; Arduini, Alessandro; Malolepsza, Edyta; Lage, Kasper; Kaushik, Virendar K; Kathiresan, Sekar; Ellinor, Patrick T
• Is Part Of: Cardiovascular research. Volume 118:Issue 13(2022)
• Page Start: 2833
• Page End: 2846
• Publication Date: 2021-11-26
• Subjects: coronary artery disease -- angiogenesis -- atherosclerosis -- endothelial cell; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Periodicals; 616.1
• DOI: 10.1093/cvr/cvab344
• Languages: English
• ISSNs: 0008-6363

Abstract

Abstract: 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.