title: Cyclic AMP Response Element Binding Protein Mediates Pathological Retinal Neovascularization via Modulating DLL4-NOTCH1 Signaling.
abstract: Retinal neovascularization is the most common cause of moderate to severe vision loss in all age groups. Despite the use of anti-VEGFA therapies, this complication continues to cause blindness, suggesting a role for additional molecules in retinal neovascularization. Besides VEGFA and VEGFB, hypoxia induced VEGFC expression robustly. Based on this finding, we tested the role of VEGFC in pathological retinal angiogenesis. VEGFC induced proliferation, migration, sprouting and tube formation of human retinal microvascular endothelial cells (HRMVECs) and these responses require CREB-mediated DLL4 expression and NOTCH1 activation. Furthermore, down regulation of VEGFC levels substantially reduced tip cell formation and retinal neovascularization in vivo. In addition, we observed that CREB via modulating the DLL4-NOTCH1 signaling mediates VEGFC-induced tip cell formation and retinal neovascularization. In regard to upstream mechanism, we found that down regulation of p38β levels inhibited hypoxia-induced CREB-DLL4-NOTCH1 activation, tip cell formation, sprouting and retinal neovascularization. Based on these findings, it may be suggested that VEGFC besides its role in the regulation of lymphangiogenesis also plays a role in pathological retinal angiogenesis and this effect depends on p38β and CREB-mediated activation of DLL4-NOTCH1 signaling.
authors: Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors: Nikhlesh K
authors: NK
authors: Singh
authors: Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors: Sivareddy
authors: S
authors: Kotla
authors: Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors: Raj
authors: R
authors: Kumar
authors: Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors: Gadiparthi N
authors: GN
authors: Rao
mesh_terms: D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D017353:Gene Deletion; D055786:Gene Knockout Techniques; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009389:Neovascularization, Pathologic; D010101:Oxygen Consumption; D011401:Promoter Regions, Genetic; D051881:Receptor, Notch1 / Q000378:metabolism*; D015861:Retinal Neovascularization / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051881:Receptor, Notch1; D042582:Vascular Endothelial Growth Factor C; C064045:delta protein; D048051:p38 Mitogen-Activated Protein Kinases
keywords: CREB; DLL4; NOTCH1; Retinal neovascularization; VEGFC