Proline-rich tyrosine kinase 2 via enhancing signal transducer and activator of transcription 3-dependent cJun expression mediates retinal neovascularization.

Abstract

Despite the involvement of proline-rich tyrosine kinase 2 (Pyk2) in endothelial cell angiogenic responses, its role in pathological retinal angiogenesis is not known. In the present study, we show that vascular endothelial growth factor A (VEGFA) induces Pyk2 activation in mediating human retinal microvascular endothelial cell (HRMVEC) migration, sprouting and tube formation. Downstream to Pyk2, VEGFA induced signal transducer and activator of transcription 3 (STAT3) activation and cJun expression in the modulation of HRMVEC migration, sprouting and tube formation. Consistent with these observations, hypoxia induced activation of Pyk2-STAT3-cJun signaling axis and siRNA-mediated downregulation of Pyk2, STAT3 or cJun levels substantially inhibited hypoxia-induced retinal endothelial cell proliferation, tip cell formation and neovascularization. Together, these observations suggest that activation of Pyk2-mediated STAT3-cJun signaling is required for VEGFA-induced HRMVEC migration, sprouting and tube formation in vitro and hypoxia-induced retinal endothelial cell proliferation, tip cell formation and neovascularization in vivo.

• Authors: Raj Kumar, Nikhlesh K Singh, Gadiparthi N Rao
• Journal: Scientific reports (Sci Rep) Vol. 6 Pg. 26480 (05 23 2016) ISSN: 2045-2322 [Electronic] England
• PMID: 27210483 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Proto-Oncogene Proteins c-jun
• STAT3 Transcription Factor
• STAT3 protein, human
• Vascular Endothelial Growth Factor A
• Focal Adhesion Kinase 2
• PTK2B protein, human

Topics

• Animals
• Cell Hypoxia
• Cell Movement (drug effects)
• Cells, Cultured
• Disease Models, Animal
• Endothelial Cells (cytology, drug effects, metabolism)
• Enzyme Activation (drug effects)
• Focal Adhesion Kinase 2 (metabolism)
• Humans
• Mice
• Proto-Oncogene Proteins c-jun (metabolism)
• Retina (cytology, drug effects, metabolism)
• Retinal Neovascularization (metabolism)
• STAT3 Transcription Factor (metabolism)
• Signal Transduction (drug effects)
• Vascular Endothelial Growth Factor A (pharmacology)