Nonvascular VEGF receptor 3 expression by corneal epithelium maintains avascularity and vision

Cursiefen, Claus; Chen, Lu; Saint‐Geniez, Magali; Hamrah, Pedram; Jin, Yiping; Rashid, Saadia; Pytowski, Bronislaw; Persaud, Kris; Wu, Yan; Streilein, J. Wayne; Dana, Reza

doi:10.1073/pnas.0506112103

Cited by 233 publications

(188 citation statements)

References 27 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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“…3). Corneal avascularity, which is a prerequisite for intact vision, is achieved by maintaining of low corneal levels of VEGF expression and strong expression of vascular endothelial growth factor receptor 3 (VEGFR-3) by corneal epithelium [48]. Up-regulation of both VEGF-C and VEGFR-3 has also been demonstrated in inflamed rat corneas [49].…”

Section: Vascular Endothelial Growth Factor (Vegf)mentioning

confidence: 99%

Analysis of protein composition and protein expression in the tear fluid of patients with congenital aniridia

Ihnatko

Edén

Lagali

et al. 2013

Journal of Proteomics

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Aniridia is a rare congenital genetic disorder caused by haploinsuffiency of the PAX6 gene, the master gene for development of the eye. The expression of tear proteins in aniridia is unknown. To screen for proteins involved in the aniridia pathophysiology, the tear fluid of patients with diagnosed congenital aniridia was examined using two-dimensional electrophoresis (2-DE) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Two-dimensional map of tear proteins in aniridia has been established and 7 proteins were differentially expressed with P less than 0.01 between aniridia patients and control subjects. Five of them were more abundant in healthy subjects, particularly alpha-enolase, peroxiredoxin 6, cystatin S, gelsolin, apolipoprotein A-1 and two other proteins, zinc-alpha 2-glycoprotein and lactoferrin were more expressed in the tears of aniridia patients. Moreover, immunoblot analysis revealed elevated levels of vascular endothelial growth factor (VEGF) in aniridia tears which is in concordance with clinical finding of pathological blood and lymph vessels in the central and peripheral cornea of aniridia patients. The proteins with different expression in patients tears may be new candidate molecules involved in the pathophysiology of aniridia and thus may be helpful for development of novel treatment strategies for the symptomatic therapy of this vision threatening condition. Biological significance This study is first to demonstrate protein composition and protein expression in aniridic tears and identifies proteins with different abundance in tear fluid from patients with congenital aniridia vs. healthy tears

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“…Upregulation of matrix-derived anti-angiogenic factors such as endostatin (Kato et al, 2003) and restin (Saika et al, 2004), along with increased anti-inflammatory factor IL-1ra may play an important role in LSC and AM transplantation-mediated anti-angiogenic effect. Recently, Cursiefen et al demonstrated a critical mechanism that contributed to corneal avascularity by VEGF receptor 3, which is normally present on lymphatic and proliferating blood vascular endothelium, is strongly constitutively expressed by corneal epithelium and is mechanistically responsible for suppressing inflammatory corneal angiogenesis (Cursiefen et al, 2006). Knowledge gained from using epithelia-matrix interaction to regulate corneal angiogenesis will enable us to optimize the anti-angiogenic effect of the cultivated cells like oral mucosal epithelial cells or mesehchymal stem cells for future ocular surface reconstruction.…”

Section: Combination Techniques With Anti-angiogenic Treatmentsmentioning

confidence: 99%