Endothelial ARHGEF26 is an angiogenic factor promoting VEGF signaling.

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 signaling and displays enhanced interactions with several proteins partially related to the angiogenic pathway. ARHGEF26 is required for endothelial angiogenesis by promoting macropinocytosis of VEGFR2 on cell membrane and is crucial to 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 an angiogenic factor, and that DNA variants within ARHGEF26 that are associated with CAD risk could affect angiogenic pathways by promoting VEGF signaling. Translational perspective Understanding the genetic architecture of coronary artery disease (CAD) is critical to developing new therapeutics. Here, we present work that revealed the causal mechanism by which DNA variants at the ARHGEF26 locus confer risk for CAD. Angiogenesis-related vascular phenotypes are associated with the ARHGEF26 locus, and ARHGEF26 promotes the angiogenic capacity of human endothelial cells.Together, our work demonstrates that ARHGEF26 is a novel angiogenic factor, and endothelial-specific inhibition of ARHGEF26 may be beneficial to treating CAD. The causal pathway and the actionable therapeutic hypotheses from our work will facilitate the development of new therapeutics for CAD.