Cyclic AMP Response Element Binding Protein Mediates Pathological Retinal Neovascularization via Modulating DLL4-NOTCH1 Signaling

Nikhlesh Singh, Sivareddy Kotla, Raj Kumar, Rao Gadiparthi

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1767-1784
Number of pages18
JournalEBioMedicine
Volume2
Issue number11
DOIs
StatePublished - Nov 1 2015

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Pathologic Neovascularization
Retinal Neovascularization
Cyclic AMP Response Element-Binding Protein
Chemical activation
Angiogenesis Inducing Agents
Endothelial cells
Down-Regulation
Lymphangiogenesis
Blindness
Molecules
Endothelial Cells
Age Groups

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Cyclic AMP Response Element Binding Protein Mediates Pathological Retinal Neovascularization via Modulating DLL4-NOTCH1 Signaling. / Singh, Nikhlesh; Kotla, Sivareddy; Kumar, Raj; Gadiparthi, Rao.

In: EBioMedicine, Vol. 2, No. 11, 01.11.2015, p. 1767-1784.

Research output: Contribution to journalArticle

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