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Cyclic AMP response element binding protein, CREB, induces endothelial cell proliferation and angiogenesis in response to thrombin
Author(s) -
Chava Koteswara Rao,
Mehta Dolly
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.956.7
Subject(s) - creb , angiogenesis , thrombin , matrigel , microbiology and biotechnology , endothelial stem cell , vascular endothelial growth factor , chemistry , transcription factor , biology , cancer research , immunology , biochemistry , in vitro , platelet , vegf receptors , gene
Thrombin rapidly increases endothelial permeability and also triggers cues to induce angiogenesis which may be important in maintaining vessel wall integrity post injury. Cyclic AMP response element binding protein (CREB) is a nuclear transcription factor which signals the angiogenesis. In this study, we investigated the role of CREB in thrombin‐induced angiogenesis. We show that in human pulmonary arterial endothelial (HPAE) cells thrombin within 5 min induced CREB phosphorylation at serine 133. CREB phosphodefective mutant blocked the thrombin‐induced angiogenesis. We show that thrombin failed to induce CREB activity in the absence of extracellular Ca2+. Based on our data that receptor‐operated Ca2+ (ROC) channels mediate Ca2+ entry in endothelial cells and we show that direct activation of ROC by oleoyl‐2‐acetyl‐sn glycerol (OAG) induced CREB phosphorylation. Knockdown of TRPC6, a prominent ROC channels in lung endothelium markedly suppressed CREB activity and also prevented thrombin induced migration and network tube formation. We show that in wild type (WT) mice subcutaneous injection of growth factor reduced matrigel induced angiogenesis while TRPC6−/− mice showed suppressed angiogenic potential. Our results identify CREB as a novel transcription factor that downstream of TRPC6 channels regulates angiogenesis thereby linking Ca2+ signaling to vascular endothelial remodeling.