Decursin inhibits VEGF-mediated inner blood-retinal barrier breakdown by suppression of VEGFR-2 activation.
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.
Kim
Jin Hyoung
JH
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.
Kim
Jeong Hun
JH
Lee
You Mie
YM
Ahn
Eun-Mi
EM
Kim
Kyu-Won
KW
Yu
Young Suk
YS
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
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