title: Decursin inhibits VEGF-mediated inner blood-retinal barrier breakdown by suppression of VEGFR-2 activation.
abstract: The blood-retinal barrier (BRB) is essential for the normal structural and functional integrity of the retina, whose breakdown could cause the serious vision loss. Vascular endothelial growth factor (VEGF), as a permeable factor, induces alteration of tight junction proteins to result in BRB breakdown. Herein, we demonstrated that decursin inhibits VEGF-mediated inner BRB breakdown through suppression of VEGFR-2 signaling pathway. In retinal endothelial cells, decursin inhibited VEGF-mediated hyperpermeability. Decursin prevented VEGF-mediated loss of tight junction proteins including zonula occludens-1 (ZO-1), ZO-2, and occludin in retinal endothelial cells, which was also supported by restoration of tight junction proteins in intercellular junction. In addition, decursin significantly inhibited VEGF-mediated vascular leakage from retinal vessels, which was accompanied by prevention of loss of tight junction proteins in retinal vessels. Decursin significantly suppressed VEGF-induced VEGFR-2 phosphrylation that consequently led to inhibition of extracellular signal-regulated kinase (ERK) 1/2 activation. Moreover, decursin induced no cytotoxicity to retinal endothelial cells and no retinal toxicity under therapeutic concentrations. Therefore, our results suggest that decursin prevents VEGF-mediated BRB breakdown through blocking of loss of tight junction proteins, which might be regulated by suppression of VEGFR-2 activation. As a novel inhibitor to BRB breakdown, decursin could be applied to variable retinopathies with BRB breakdown.
authors.affiliation: Fight against Angiogenesis-Related Blindness (FARB) Laboratory, Department of Ophthalmology, College of Medicine, Seoul National University and Seoul Artificial Eye Center Clinical Research Institute, Seoul National University Hospital, Seoul, Korea.
authors.forename: Jin Hyoung
authors.initials: JH
authors.lastname: Kim
authors.forename: Jeong Hun
authors.initials: JH
authors.lastname: Kim
authors.forename: You Mie
authors.initials: YM
authors.lastname: Lee
authors.forename: Eun-Mi
authors.initials: EM
authors.lastname: Ahn
authors.forename: Kyu-Won
authors.initials: KW
authors.lastname: Kim
authors.forename: Young Suk
authors.initials: YS
authors.lastname: Yu
mesh_terms: D000818:Animals; D001578:Benzopyrans / Q000378:metabolism*; D001813:Blood-Retinal Barrier / Q000502:physiology*; D002087:Butyrates / Q000378:metabolism*; D002199:Capillary Permeability; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation; D062793:Occludin; D010750:Phosphoproteins / Q000378:metabolism; D012160:Retina / Q000166:cytology / Q000378:metabolism; D019108:Tight Junctions / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*; D062826:Zonula Occludens-1 Protein; D062827:Zonula Occludens-2 Protein
chemical_list: D001578:Benzopyrans; D002087:Butyrates; D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; C568986:Ocln protein, mouse; D010750:Phosphoproteins; C569042:TJP1 protein, human; C569046:TJP2 protein, human; C569043:Tjp1 protein, mouse; C569047:Tjp2 protein, mouse; D042461:Vascular Endothelial Growth Factor A; D062826:Zonula Occludens-1 Protein; D062827:Zonula Occludens-2 Protein; C101278:decursin; D040301:Vascular Endothelial Growth Factor Receptor-2