Abstract
The tyrosine kinase receptor vascular endothelial growth factor receptor 2 (VEGFR2) is a critical modulator of angiogenesis. Increasing evidence indicate the important role of bromodomain and extra-terminal domain (BET) of chromatin adaptors in regulating tumor growth and inflammatory response. However, whether BET proteins have a role in angiogenesis and endothelial permeability is unclear. In this study, we observed that treatment with JQ1, a specific BET inhibitor, suppressed in vitro tube formation of human umbilical vein endothelial cells (HUVECs) and in vivo angiogenesis in a Matrigel plug and oxygen-induced retinopathy neovascularization. JQ1 attenuated the VEGF-induced decrease in TEER in HUVECs and prevented Evans blue dye leakage in the VEGF-induced Miles assay in athymic Balb/c nude mice. BET inhibition with JQ1 or shRNA for Brd2 or Brd4 suppressed VEGF-induced migration, proliferation, and stress fiber formation of HUVECs. Furthermore, BET inhibition suppressed phosphorylation of VEGFR2 and PAK1, as well as eNOS activation in VEGF-stimulated HUVECs. Inhibition with VEGFR2 and PAK1 also reduced migration and proliferation, and attenuated the VEGF-induced decrease in TEER. Thus, our observations suggest the important role of BET bromodomain in regulating VEGF-induced angiogenesis. Strategies that target the BET bromodomain may provide a new therapeutic approach for angiogenesis-related diseases.
Highlights
The tyrosine kinase receptor vascular endothelial growth factor receptor 2 (VEGFR2) is a critical modulator of angiogenesis
We demonstrated for the first time that bromodomain and extraterminal domain (BET) bromodomain inhibition suppressed VEGF-induced angiogenesis and endothelial permeability in vitro and in vivo
We showed that BET inhibition suppressed VEGF-induced endothelial VEGFR2/PAK1 activation
Summary
The tyrosine kinase receptor vascular endothelial growth factor receptor 2 (VEGFR2) is a critical modulator of angiogenesis. We observed that treatment with JQ1, a specific BET inhibitor, suppressed in vitro tube formation of human umbilical vein endothelial cells (HUVECs) and in vivo angiogenesis in a Matrigel plug and oxygen-induced retinopathy neovascularization. Our observations suggest the important role of BET bromodomain in regulating VEGF-induced angiogenesis. VEGF-mediated stimulation of vascular endothelial growth factor receptor 2 (VEGFR2), a type II transmembrane tyrosine kinase receptor expressed on endothelial cells and on circulating bone marrow-derived endothelial progenitor cells, results in activation of several signaling pathways, which regulate a variety of endothelial functions including endothelial survival, migration, permeability, and proliferation[4,5,6]. Endothelial nitric oxide synthase (eNOS), which generates nitric oxide (NO), plays an important role in mediating angiogenesis and vascular permeability[16]
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