Endothelial ARHGEF26 is an angiogenic factor promoting VEGF signalling

Qiuyu Martin Zhu; Bryan T MacDonald; Taiji Mizoguchi; Mark Chaffin; Alison Leed; Alessandro Arduini; Edyta Malolepsza; Kasper Lage; Virendar K Kaushik; Sekar Kathiresan; Patrick T Ellinor

doi:10.1093/cvr/cvab344

Endothelial ARHGEF26 is an angiogenic factor promoting VEGF signalling

Cardiovasc Res. 2022 Oct 21;118(13):2833-2846. doi: 10.1093/cvr/cvab344.

Authors

Qiuyu Martin Zhu^{1

2

3}, Bryan T MacDonald¹, Taiji Mizoguchi^{1

3}, Mark Chaffin¹, Alison Leed⁴, Alessandro Arduini¹, Edyta Malolepsza⁵, Kasper Lage^{6

7}, Virendar K Kaushik⁴, Sekar Kathiresan^{1

2

8}, Patrick T Ellinor^{1

3}

Affiliations

¹ Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, 75 Ames Street, Cambridge, MA 02142, USA.
² Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
³ Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
⁴ Center for the Development of Therapeutics, The Broad Institute of Harvard and MIT, Cambridge, MA, USA.
⁵ Genomics Platform, The Broad Institute of Harvard and MIT, Cambridge, MA, USA.
⁶ Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁷ Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁸ Verve Therapeutics, Cambridge, MA, USA.

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.

Keywords: angiogenesis; atherosclerosis; coronary artery disease; endothelial cell.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Guanine Nucleotide Exchange Factors* / genetics
Humans
Mice
Neovascularization, Pathologic
Neovascularization, Physiologic / physiology
Signal Transduction
Vascular Endothelial Growth Factor A / metabolism
Vascular Endothelial Growth Factor Receptor-2* / metabolism

Substances

Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factor Receptor-2
ARHGEF26 protein, human
Guanine Nucleotide Exchange Factors
KDR protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding