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Endothelial ARHGEF26 is an angiogenic factor promoting VEGF signalling.
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.
Afiliación
  • Zhu QM; Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, 75 Ames Street, Cambridge, MA 02142, USA.
  • MacDonald BT; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Mizoguchi T; 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; Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, 75 Ames Street, Cambridge, MA 02142, USA.
  • Arduini A; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
  • Malolepsza E; Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, 75 Ames Street, Cambridge, MA 02142, USA.
  • Lage K; Center for the Development of Therapeutics, The Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Kaushik VK; Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, 75 Ames Street, Cambridge, MA 02142, USA.
  • Kathiresan S; Genomics Platform, The Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Ellinor PT; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Cardiovasc Res ; 118(13): 2833-2846, 2022 10 21.
Article en En | MEDLINE | ID: mdl-34849650
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factores de Intercambio de Guanina Nucleótido / Receptor 2 de Factores de Crecimiento Endotelial Vascular Límite: Animals / Humans Idioma: En Revista: Cardiovasc Res Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factores de Intercambio de Guanina Nucleótido / Receptor 2 de Factores de Crecimiento Endotelial Vascular Límite: Animals / Humans Idioma: En Revista: Cardiovasc Res Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido