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Inhibitory Effect of Slit2-N on VEGF165-induced proliferation of vascular endothelia via Slit2-N-Robo4-Akt pathway in choroidal neovascularization.

ABSTRACT: Researches have been focusing on the role of Slit2 in angiogenesis, specifically in cell migration and vessel permeability. Nevertheless, the role of Slit2-N, the bioactive fragment of Slit2, in the proliferation of vascular endothelia in choroidal neovascularization and some related mechanisms have not been studied yet. Thus, our study aimed to explore the role of Slit2-N in proliferation of vascular endothelia and the related mechanisms in choroidal neovascularization. Fluorescein isothiocyanate perfusion and HE staining were performed to evaluate volumes of choroidal neovascularization lesions. The effect of Slit2-N on VEGF165-induced cell proliferation and some related mechanisms were detected by CCK8 assay, flow cytometry, siRNA transfection, and western blotting. We found that Slit2-N reduced volumes of laser-induced choroidal neovascularization networks in vivo. Results of the in vitro study showed Slit2-N reduced VEGF165-induced cell proliferation of both human umbilical vascular endothelial cells and human microvascular endothelial cells possibly via activation of AKT rather than that of ERK1/2. Additionally, Robo4, one of the receptors binding to Slit2-N, was involved in the inhibitory effect of Slit2-N. Generally, our findings revealed the inhibitory role of Slit2-N in proliferation of vascular endothelia and some related mechanisms, and presented some potential targets, molecules along Slit2-N-Robo4-AKT axis, to choroidal neovascularization therapy.

SUBMITTER: Jiang S

PROVIDER: S-EPMC6592260 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Inhibitory Effect of Slit2-N on VEGF165-induced proliferation of vascular endothelia via Slit2-N-Robo4-Akt pathway in choroidal neovascularization.

Jiang Shaoqiu S Du Yong Y Liu Danning D He Junchi J Huang Yike Y Qin Ke K Zhou Xiyuan X

Cell cycle (Georgetown, Tex.) 20190522 11

Researches have been focusing on the role of Slit2 in angiogenesis, specifically in cell migration and vessel permeability. Nevertheless, the role of Slit2-N, the bioactive fragment of Slit2, in the proliferation of vascular endothelia in choroidal neovascularization and some related mechanisms have not been studied yet. Thus, our study aimed to explore the role of Slit2-N in proliferation of vascular endothelia and the related mechanisms in choroidal neovascularization. Fluorescein isothiocyana ...[more]

PMID: 31081721

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Project description:PurposeAge-related macular degeneration (AMD) is the leading cause of central visual loss among patients over the age of 55 years worldwide. Neovascular-type AMD (nAMD) accounts for approximately 10% of patients with AMD and is characterized by choroidal neovascularization (CNV). The proliferation of choroidal endothelial cells (CECs) is one important step in the formation of new vessels. Transcriptional coactivator Yes-associated protein (YAP) can promote the proliferation of multiple cancer cells, corneal endothelial cells, and vascular smooth muscle cells, which participate in angiogenesis. This study intends to reveal the expression and functions of YAP during the CNV process.MethodsIn the study, a mouse CNV model was generated by laser photocoagulation. YAP expression was detected with western blotting and immunohistochemistry. YAP siRNA and ranibizumab, a VEGF monoclonal antibody, were injected intravitreally in CNV mice. The YAP and VEGF expression levels after injection were detected with western blotting. The incidence and leakage area of CNV were measured with fundus fluorescein angiography, choroidal flat mounting, and hematoxylin and eosin (HE) staining. Immunofluorescent double staining was used to detect YAP cellular localization with CD31 (an endothelial cell marker) antibody. Proliferating cell nuclear antigen (PCNA) expression in CNV mice without or with YAP siRNA intravitreal injection and the colocalization of PCNA and CD31 were measured with western blotting and immunofluorescent double staining, respectively.ResultsYAP expression increased following laser exposure, in accordance with vascular endothelial growth factor (VEGF) expression. YAP siRNA and ranibizumab decreased VEGF expression and the incidence and leakage area of CNV. YAP was localized in the vascular endothelium within the CNV site. Additionally, after laser exposure, YAP siRNA inhibited the increased expression of PCNA, which was colocalized with endothelial cells.ConclusionsThis study showed that YAP upregulation promoted CNV formation by upregulating the proliferation of endothelial cells, providing evidence for the molecular mechanisms of CNV and suggesting a novel molecular target for nAMD treatment.

Dataset Information

Inhibitory Effect of Slit2-N on VEGF165-induced proliferation of vascular endothelia via Slit2-N-Robo4-Akt pathway in choroidal neovascularization.

Publications

Inhibitory Effect of Slit2-N on VEGF165-induced proliferation of vascular endothelia via Slit2-N-Robo4-Akt pathway in choroidal neovascularization.

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