Corneal avascularity is due to soluble VEGF receptor-1

Ambati, Balamurali K.; Nozaki, Miho; Singh, Nirbhai; Takeda, Atsunobu; Jani, Pooja D.; Suthar, Tushar; Albuquerque, Romulo; Richter, Elizabeth R.; Sakurai, Eiji; Newcomb, Michael T.; Kleinman, Mark E.; Caldwell, Ruth B.; Lin, Qing; Ogura, Yuichiro; Orecchia, Angela; Samuelson, Don; Agnew, Dalen; Leger, Judy St.; Green, W. Richard; Mahasreshti, Parameshwar J.; Curiel, David T.; Kwan, Donna; Marsh, Helene; Ikeda, Shinya; Leiper, Lucy J.; Collinson, J. Martin; Bogdanovich, Sasha; Khurana, Tejvir S.; Shibuya, Masabumi; Baldwin, Megan E.; Ferrara, Napoleone; Gerber, Hans Peter; Falco, Sandro De; Witta, Jassir; Baffi, Judit; Raisler, Brian J.; Ambati, Jayakrishna

doi:10.1038/nature05249

Cited by 585 publications

(503 citation statements)

References 25 publications

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“…These mechanisms include an intact corneal epithelial layer; soluble immunomodulatory factors in the aqueous humor, the blood-ocular barrier; epithelial expression of membrane and soluble vascular endothelial growth factor receptors (VEGFRs) 1,2 ; and the high expression of Fas ligand and thrombospondin-1. [3][4][5][6] Recently, another immunoregulatory molecule, programmed death ligand-1 (PD-L1, also known as CD274 or B7-H1), has been shown to be expressed at high levels by corneal tissue by our laboratory and others.…”

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confidence: 99%

A Novel Function for Programmed Death Ligand-1

Jin

Chauhan

Annan

et al. 2011

The American Journal of Pathology

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Programmed death ligand-1 (PD-L1) plays a critical role in T-cell regulatory function. Here, we report a newly discovered effect of PD-L1 on angiogenesis. We demonstrate that PD-L1 and its receptor CD80, but not PD-1, are expressed by primary murine lung and heart vascular endothelial cells and the miscrovascular endothelial cell line (MS1) at both the mRNA and protein levels in vitro. The inhibition of PD-L1 or CD80 expression in MS1 cells, by small-interfering RNA transfection, led to a significant up-regulation of vascular endothelial growth factor receptor 2 expression and cell proliferation levels in MS1 cells. Furthermore, MS1 cells were found to have a significantly lower proliferation and vascular endothelial growth factor receptor 2 expression levels when they were co-cultured with PD-L1-expressing normal corneal epithelial cells, as compared to MS1 cells co-cultured with PD-L1 ؊/؊ corneal epithelial cells. In a sutureinduced corneal angiogenesis model, we observed a significantly higher level of angiogenic response in PD-L1 ؊/؊ knockout mice as compared to wild-type mice, although there was no significant difference in the expression of inflammatory cytokines (interleukin-1␣, interleukin-1␤, or tumor necrosis factor-␣) or the infiltration of innate immune cells (neutrophils and macrophages) between the two groups. We conclude that the expression of PD-L1 in both vascular endothelial cells and corneal epithelial cells regulates corneal angiogenesis.

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confidence: 99%

A Novel Function for Programmed Death Ligand-1

Jin

Chauhan

Annan

et al. 2011

The American Journal of Pathology

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“…29 This requires tight regulation of the vascular growth process in avascular corneal tissue, which is maintained by the expression of soluble VEGF receptor-1 (sFlt-1). 30 Under certain inflammatory conditions, however, avascular cornea may be subject to unwanted new blood vessel growth from the limbus caused by the loss of the limbal stem cell barrier.…”

Section: Discussionmentioning

confidence: 99%

Subconjunctival gene delivery of the transcription factor GA-binding protein delays corneal neovascularization in a mouse model

et al. 2009

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Corneal neovascularization can reduce visual acuity. GAbinding protein (GABP) is a transcription factor that regulates the expression of target genes including vascular endothelial growth factor (VEGF) and roundabout4 (Robo4), which participate in pathologic angiogenesis. We assessed whether intraocular injection of the GABP gene affects the growth of new corneal blood vessels in a mouse ocular neovascularization model. Transfection of human GABPa and GABPb gene (GABPa/b) into human conjunctival epithelial cells resulted in decreased VEGF and Robo4 expression. Three groups of mice underwent chemical and mechanical denudation of the corneal epithelium. Subsequently, two groups were administered subconjunctival injection of lipoplexes carrying plasmid DNA encoding for human GABPa/b or an empty plasmid DNA at 1-week intervals. The third group served as an experimental control. In vivo delivery of human GABPa/b into mouse neovascularized cornea reduced VEGF and Robo4 gene expression. Biomicroscopic examination showed that, at 1 week after one or two injections, GABPa/b-treated eyes had significantly less neovascularized corneal area than did eyes treated with the empty vector. Histologic examination showed significantly less vascularized area and fewer blood vessels in the GABP-treated group at 1 week after injections. However, these angiosuppressive effects were weakened at 2 weeks after injections. Our results indicate that subconjunctival GABP gene delivery delays corneal neovascularization for up to 2 weeks in a mouse model of deliberate corneal injury.

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“…Several secreted proteins have been reported to bind and sequester VEGF (Kendall and Thomas, 1993;Gengrinovitch et al, 1995;Gupta et al, 1999;Inoki et al, 2002;Luque et al, 2003). This type of regulation could account for the vascular quiescence in the presence of VEGF, although in most tissues except the cornea (Ambati et al, 2006), the relevance of these proteins to vascular control has yet to be demonstrated.…”

Section: Introductionmentioning

confidence: 99%