Prevention of VEGF-induced growth and tube formation in human retinal endothelial cells by aldose reductase inhibition |
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| Authors: | Yadav Umesh C S Srivastava Satish K Ramana Kota V |
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| Institution: | 3. Departments of Biochemistry and Structural Biology;5. Cellular and Integrative Physiology, University of Texas Health Science Center, San Antonio, Texas 78229;4. Second Xiangya Hospital, Central South University, Changsha 410011, China;3. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China;4. Eye Center of the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, China;1. Institute of Biocolloidal Chemistry (named after F.D. Ovcharenko), NAS of Ukraine, 42, blvr. Vernadskogo, Kyiv 03142, Ukraine;2. Taras Shevchenko Kiev National University, Department of Physics, 2, av. Academician Glushkov, Kyiv 031127, Ukraine;1. Harvard Ophthalmology, Schepens Eye Research Institute of Massachusetts Eye and Ear, Boston, MA, USA;2. Department of Health Technology, Institut for Sundhedsteknologi, Lyngby, Denmark;3. Department of Cancer Biology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA, 02215, USA |
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| Abstract: | ObjectiveSince diabetes-induced vascular endothelial growth factor (VEGF) is implicated in retinal angiogenesis, we aimed to examine the role of aldose reductase (AR) in VEGF-induced human retinal endothelial cells (HREC) growth and tube formation.Materials and MethodsHRECs were stimulated with VEGF and cell-growth was determined by MTT assay. AR inhibitor, fidarestat, to block the enzyme activity and AR siRNA to ablate AR gene expression in HREC were used to investigate the role of AR in neovascularization using cell-migration and tube formation assays. Various signaling intermediates and angiogenesis markers were assessed by Western blot analysis. Immuno-histochemical analysis of diabetic rat eyes was performed to examine VEGF expression in the retinal layer.ResultsStimulation of primary HREC with VEGF caused increased cell growth and migration, and AR inhibition with fidarestat or ablation with siRNA significantly prevented it. VEGF-induced tube formation in HREC was also significantly prevented by fidarestat. Treatment of HREC with VEGF also increased the expression of VCAM, AR, and phosphorylation and activation of Akt and p38-MAP kinase, which were prevented by fidarestat. VEGF-induced expression of VEGFRII in HREC was also prevented by AR inhibition or ablation.ConclusionsOur results indicate that inhibition of AR in HREC prevents tube formation by inhibiting the VEGF-induced activation of the Akt and p38-MAPK pathway and suggest a mediatory role of AR in ocular neovascularization generally implicated in retinopathy and AMD. |
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