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MMP14 Regulates VEGFR3 Expression on Corneal Epithelial Cells
Kyu-Yeon Han, Jin-Hong Chang1, Dimitri T Azar
1Department of Ophthalmology and Visual Sciences, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612. changr@uic.edu.
Abstract:
Vascular endothelial growth factor receptor 3 (VEGFR3) regulates the growth and differentiation of blood and lymphatic vessels. To determine whether matrix metalloproteinase 14 (MMP14) modulates VEGFR3 expression in the corneal epithelium to influence the avascularity of the cornea, VEGFR3 expression was compared between wild-type and MMP14-deficient (MMP14 Δexon4) corneal epithelial cells. Western blot analysis showed that VEGFR3 protein expression was higher on MMP14 Δexon4 corneal epithelial cells than on wild-type cells, and quantitative RT-PCR analysis showed that VEGFR3 gene expression was highly induced in MMP14 Δexon4 corneal epithelial cells but not in wild-type corneal epithelial cells or wild-type and MMP14 Δexon4 corneal keratocytes. Unlike in epithelial cells, MMP14 Δexon4 keratocytes did not express relatively higher levels of VEGFR3 than wild-type keratocytes. Interestingly, in vitro proteolysis experiments showed that MMP14 does not cleave VEGFR3 in vitro as it does VEGFR1, indicating that other genes may be involved in the modulation of VEGFR3 expression by MMP14. Using proteomic analysis to identify candidate factors, we found that 39 nuclear proteins were differentially expressed between wildtype and MMP14 Δexon4 corneal epithelial cells. These findings suggest that MMP14 may regulate VEGFR3 expression at the transcriptional level on corneal epithelial cells but not on corneal keratocytes.
Insights
Matrix metalloproteinase 14 (MMP14) deficiency increases vascular endothelial growth factor receptor 3 (VEGFR3) expression in corneal epithelial cells, suggesting MMP14 regulates VEGFR3 transcription. This finding impacts understanding corneal avascularity.
Area of Science:
- Ophthalmology
- Molecular Biology
- Cell Biology
Background:
- Vascular endothelial growth factor receptor 3 (VEGFR3) is crucial for blood and lymphatic vessel development.
- Corneal avascularity is essential for maintaining vision clarity.
- Matrix metalloproteinase 14 (MMP14) is a protease implicated in tissue remodeling.
Purpose of the Study:
- To investigate if matrix metalloproteinase 14 (MMP14) influences vascular endothelial growth factor receptor 3 (VEGFR3) expression in corneal epithelial cells.
- To determine the role of MMP14 in regulating corneal avascularity through VEGFR3 modulation.
Main Methods:
- Western blot analysis to compare VEGFR3 protein levels in wild-type and MMP14-deficient corneal epithelial cells.
- Quantitative RT-PCR to assess VEGFR3 gene expression.
- In vitro proteolysis assays to test direct cleavage of VEGFR3 by MMP14.
- Proteomic analysis to identify differentially expressed nuclear proteins.
Main Results:
- VEGFR3 protein and gene expression were significantly higher in MMP14-deficient corneal epithelial cells compared to wild-type.
- MMP14 deficiency did not affect VEGFR3 expression in corneal keratocytes.
- MMP14 did not directly cleave VEGFR3 in vitro.
- Proteomic analysis revealed differential expression of 39 nuclear proteins between wild-type and MMP14-deficient corneal epithelial cells.
Conclusions:
- MMP14 appears to regulate VEGFR3 expression at the transcriptional level in corneal epithelial cells.
- The mechanism of MMP14's regulation of VEGFR3 in epithelial cells may involve nuclear protein modulation, not direct cleavage.
- These findings suggest a novel pathway influencing corneal avascularity.
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