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Thrombin-induced VEGF expression in human retinal pigment epithelial cells
Zong-Mei Bian1, Susan G Elner, Victor M Elner
1Department of Ophthalmology, University of Michigan, Ann Arbor, Michigan 48105, USA.
Investigative Ophthalmology & Visual Science
|May 26, 2007
Summary
Thrombin significantly increases VEGF expression in retinal pigment epithelial (RPE) cells, involving multiple signaling pathways and calcium mobilization, especially when combined with TGF-beta2.
Area of Science:
- Molecular Biology
- Cell Biology
- Ophthalmology
Background:
- Vascular Endothelial Growth Factor (VEGF) is crucial for angiogenesis.
- Retinal Pigment Epithelial (RPE) cells play a role in ocular health and disease.
- Thrombin's role in modulating VEGF expression in RPE cells is not fully understood.
Purpose of the Study:
- To investigate the effects of thrombin on VEGF expression in human RPE (hRPE) cells.
- To examine the synergistic effects of thrombin with other proangiogenic factors (TNF-alpha, monocytes, TGF-beta2) on VEGF expression.
Main Methods:
- hRPE cells were stimulated with thrombin, TNF-alpha, monocytes, and TGF-beta2.
- VEGF expression was analyzed using ELISA, Western blot, immunocytochemistry, and RT-PCR.
- Signal transduction pathways were elucidated using specific inhibitors and calcium chelators.
Main Results:
- Thrombin treatment dose- and time-dependently increased VEGF mRNA and protein in hRPE cells, primarily via protease-activated receptor (PAR)-1.
- VEGF induction by thrombin involved multiple pathways including MAPK/ERK, p38, JNK, PTK, PI3K, PKC, NF-kappaB, and ROS.
- Combinations of thrombin with TNF-alpha or monocytes showed additive VEGF induction, while thrombin with TGF-beta2 exhibited synergistic effects, significantly amplified by calcium mobilization.
Conclusions:
- Thrombin potently stimulates VEGF expression in hRPE cells, both alone and in combination with other factors, through diverse signaling pathways.
- Thrombin-induced calcium mobilization is critical for maximizing TGF-beta2-mediated VEGF expression in RPE cells, suggesting a key role in ocular angiogenesis.
