Corneal lymphangiogenesis follows severe corneal injuries and infections and is one of the major causes of blindness. Under normal physiological conditions, the cornea is alymphatic and surrounded by lymphatic vessels residing in the conjunctiva while corneal lymphangiogenic privilege is maintained. However, wounding and infection induce corneal lymphangiogenesis. The extrinsic factors that regulate corneal lymphangiogenic privilege include: 1) the presence of angiogenic and lymphangiogenic factors (VEGF-A, -C and -D);2) expression of sVEGFR-2 in the cornea;3) expression of VEGFR-3 in corneal epithelium and other anti-lymphangiogenic factors in the cornea. The status of corneal lymphangiogenesis is controlled by the balance of pro- and anti- lymphatic factors. The current hypothesis of corneal lymphangiogenic privilege is governed by extrinsic factors unique to the cornea. Besides the well-documented extrinsic factors involved in regulating corneal lymphangiogenic privilege, changes in the VEGFR-2 may regulate VEGFR3-activation in lymphatic cells also regulate corneal lymphangiogenesis. Our preliminary data demonstrated corneal lymphangiogenesis in diseased human corneas, which correlated with enhanced VEGFR-3 expression in alkali-burn-wounded corneas. In addition, endostatin-containing fragments bind to VEGFR-3 in vitro and have better inhibition of bFGF-induced corneal lymphangiogenesis than angiogenesis. VEGF- C-induced VEGFR-3 dimerization and low dose VEGF-C has better potency in promoting lymphatic cell proliferation. Our long-term objective is to identify the mechanisms that regulate corneal lymphangiogenesis. The proposed experiments are designed to determine the role of VEGF-C-induced VEGFR-3 homodimerization regulated by VEGF-2/-3 heterodimerization and to investigate selective inhibitors for the inhibition of VEGFR-3 homodimerization during corneal lymphangiogenesis.

Public Health Relevance

Lymphangiogenesis is the process of increased production of lymphatic vessels and can be both physiological and pathological. We hypothesize that VEGFR-2 interferes with VEGFR-3 dimerization may play a role in the regulation of corneal lymphangiogenesis. Understanding the molecular mechanisms of corneal lymphangiogenesis will provide novel therapeutic interventions in the treatment of lymphangiogenesis-related disorders.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21EY021886-02
Application #
8309043
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Shen, Grace L
Project Start
2011-08-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2012
Total Cost
$199,375
Indirect Cost
$74,375
Name
University of Illinois at Chicago
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
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Chang, Jin-Hong; Putra, Ilham; Huang, Yu-Hui et al. (2016) Limited versus total epithelial debridement ocular surface injury: Live fluorescence imaging of hemangiogenesis and lymphangiogenesis in Prox1-GFP/Flk1::Myr-mCherry mice. Biochim Biophys Acta 1860:2148-56
Han, Kyu-Yeon; Dugas-Ford, Jennifer; Lee, Hyun et al. (2015) MMP14 Cleavage of VEGFR1 in the Cornea Leads to a VEGF-Trap Antiangiogenic Effect. Invest Ophthalmol Vis Sci 56:5450-6
Kim, Megan; Lee, Chelsea; Payne, Rachael et al. (2015) Angiogenesis in glaucoma filtration surgery and neovascular glaucoma: A review. Surv Ophthalmol 60:524-35
Park, Paul J; Chang, Michael; Garg, Nitin et al. (2015) Corneal lymphangiogenesis in herpetic stromal keratitis. Surv Ophthalmol 60:60-71
Zhu, Jimmy; Dugas-Ford, Jennifer; Chang, Michael et al. (2015) Simultaneous in vivo imaging of blood and lymphatic vessel growth in Prox1-GFP/Flk1::myr-mCherry mice. FEBS J 282:1458-67
Walia, Amit; Yang, Jessica F; Huang, Yu-Hui et al. (2015) Endostatin's emerging roles in angiogenesis, lymphangiogenesis, disease, and clinical applications. Biochim Biophys Acta 1850:2422-38
Han, Kyu-Yeon; Chang, Jin-Hong; Dugas-Ford, Jennifer et al. (2014) Involvement of lysosomal degradation in VEGF-C-induced down-regulation of VEGFR-3. FEBS Lett 588:4357-63
Gonzalez, Lilian; Loza, Raymond J; Han, Kyu-Yeon et al. (2013) Nanotechnology in corneal neovascularization therapy--a review. J Ocul Pharmacol Ther 29:124-34
Han, Kyu-Yeon; Fahd, Daoud C; Tshionyi, Makambo et al. (2012) MT1-MMP modulates bFGF-induced VEGF-A expression in corneal fibroblasts. Protein Pept Lett 19:1334-9

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