Corneal neovascularization (NV) is a major cause of blindness worldwide. Toward the overall goal of identifying a molecular target for blocking corneal NV, the objective of the proposed research is to determine the role of membrane type 1 matrix metalloproteinase (MT1-MMP) activity, and specifically its proteolytic functions, in corneal NV. Our laboratory has found that MT1-MMP increases vascular endothelial growth factor (VEGF)-A?induced ERK phosphorylation in a time- and concentration-dependent manner in vascular endothelial cells. Aortic ring assays showed diminished vessel sprouting in vitro in response to VEGF-A stimulation, but not to basic fibroblast growth factor (bFGF) stimulation, in mice with conditional deletion of vascular MT1-MMP as compared to that in control mice. In addition, diminished VEGF-A?induced corneal angiogenesis was seen in vivo in mice with conditional deletion of vascular MT1-MMP compared with that in control mice. We hypothesize that limbal microvascular endothelial cell-associated MT1-MMP is required for VEGF-A?mediated corneal NV and that MT1-MMP promotes corneal NV by three novel mechanisms: (i) MT1-MMP binds to, and degrades, VEGF receptor 1 (VEGFR1) on limbal microvascular endothelial cells (Aim A); (ii) MT1-MMP degradation of VEGFR1 on invading limbal microvascular endothelial cells potentiates pro-MMP2 activation and thereby increases its collagenolytic activity (Aim B); and (iii) enzymatically-active MT1-MMP tethered to stromal fibroblast-derived exosomes promotes VEGFR1 degradation on limbal vascular endothelial cells (Aim C). Spatial and temporal characterization of MT1-MMP activity in corneal angiogenesis and evaluation of the proposed mechanisms of corneal NV will be valuable for the treatment of corneal NV and for identifying potential targets for therapeutic intervention in ocular and systemic conditions involving angiogenesis.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-BDCN-J (91)S)
Program Officer
Mckie, George Ann
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Illinois at Chicago
Schools of Medicine
United States
Zip Code
Zhong, Wei; Montana, Mario; Santosa, Samuel M et al. (2018) Angiogenesis and lymphangiogenesis in corneal transplantation-A review. Surv Ophthalmol 63:453-479
Yamakawa, Michael; Doh, Susan J; Santosa, Samuel M et al. (2018) Potential lymphangiogenesis therapies: Learning from current antiangiogenesis therapies-A review. Med Res Rev 38:1769-1798
Zhong, Wei; Gao, Xinbo; Wang, Shuangyong et al. (2017) Prox1-GFP/Flt1-DsRed transgenic mice: an animal model for simultaneous live imaging of angiogenesis and lymphangiogenesis. Angiogenesis 20:581-598
Giri, Pushpanjali; Azar, Dimitri T (2017) Risk profiles of ectasia after keratorefractive surgery. Curr Opin Ophthalmol 28:337-342
Han, Kyu-Yeon; Tran, Jennifer A; Chang, Jin-Hong et al. (2017) Potential role of corneal epithelial cell-derived exosomes in corneal wound healing and neovascularization. Sci Rep 7:40548
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; Chang, Jin-Hong; Lee, Hyun et al. (2016) Proangiogenic Interactions of Vascular Endothelial MMP14 With VEGF Receptor 1 in VEGFA-Mediated Corneal Angiogenesis. Invest Ophthalmol Vis Sci 57:3313-22
Yang, Jessica F; Walia, Amit; Huang, Yu-hui et al. (2016) Understanding lymphangiogenesis in knockout models, the cornea, and ocular diseases for the development of therapeutic interventions. Surv Ophthalmol 61:272-96
Han, Kyu-Yeon; Chang, Michael; Ying, Hong-Yu et al. (2015) Selective Binding of Endostatin Peptide 4 to Recombinant VEGF Receptor 3 In Vitro. Protein Pept Lett 22:1025-30
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

Showing the most recent 10 out of 37 publications