Corneal neovascularization (NV) is a common, disabling condition and a major cause of blindness that can follow corneal injury or infection. Our long term goal is to characterize the role of VEGF receptors in the two central corneal vascularization processes, vascular angiogenesis (VA) and lymphangiogenesis (LA). The involvement of the epithelial, soluble form of VEGFR-2 (sVEGFR-2) in LA has been well characterized. However, the role of membrane- bound, vascular VEGFR-2 (mbVEGFR-2) in corneal VA and LA has not. These proposed experiments are designed to characterize the potential angiogenic and lymphangiogenic roles of the membrane bound isoform of VEGFR-2. We propose the hypothesis that vascular mbVEGFR2 may have distinct roles, separate from those of VEGFR1 or VEGFR3, in response to induction by VEGF-A (towards VA) or VEGF-C (towards LA) in corneal angiogenesis/ lymphangiogenesis.
Two specific aims have been proposed to characterize the role of VEGFR- 2 in corneal angiogenesis and lymphangiogenesis.
Aim A. Use inducible, conditional knockout mouse lines to determine whether mbVEGFR2 maintains a counterbalanced relationship with sVEGFR1 and sVEGFR2 in the cornea.
Aim B. Characterize the individual roles of pro- angiogenic agents on VEGFR activity and VA/LA initiation, progression, and maintenance. SIGNIFICANCE: The endothelial receptor mbVEGFR2 sits at the crossroads of VA/LA initiation. Our proposed research strategy will define the role mbVEGFR2 plays in maintaining the vascular/avascular balance at the corneal border in both the normal and injured eye, increase our understanding of the VEGFR2-R3 relationship, and separate the relative contributions of pro-angiogenic agents and mbVEGFR2 to proliferation, migration, and tube formation. A better understanding of the role this receptor plays in both the normal and injured eye is of clinical importance because it increases our ability to develop therapeutic methods to prevent or reverse pathological VA and LA in the cornea, in other transplant procedures, and in tumor growth and metastasis.
Angiogenesis and lymphangiogenesis are the processes that increase production of blood and lymphatic vessels;both can be physiologically necessary and pathological. We hypothesize that VEGFR-2 plays an important role in the regulation of corneal angiogenesis and lymphangiogenesis. Understanding the molecular mechanisms of corneal angiogenesis and lymphangiogenesis will provide novel therapeutic interventions in the treatment of angiogenesis and lymphangiogenesis-related disorders.
|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|