Retinal pigment epithelium‐derived transforming growth factor‐β2 inhibits the angiogenic response of endothelial cells by decreasing vascular endothelial growth factor receptor‐2 expression

Abstract

Transforming growth factor-β (TGF-β) is a multifunctional cytokine that is known to modulate various aspects of endothelial cell (EC) biology. Retinal pigment epithelium (RPE) is important for regulating angiogenesis of choriocapillaris and one of the main cell sources of TGF-β secretion, particularly TGF-β2. However, it is largely unclear whether and how TGF-β2 affects angiogenic responses of ECs. In the current study, we demonstrated that TGF-β2 reduces vascular endothelial growth factor receptor-2 (VEGFR-2) expression in ECs and thereby inhibits vascular endothelial growth factor (VEGF) signaling and VEGF-induced angiogenic responses such as EC migration and tube formation. We also demonstrated that the reduction of VEGFR-2 expression by TGF-β2 is due to the suppression of JNK signaling. In coculture of RPE cells and ECs, RPE cells decreased VEGFR-2 levels in ECs and EC migration. In addition, we showed that TGF-β2 derived from RPE cells is involved in the reduction of VEGFR-2 expression and inhibition of EC migration. These results suggest that TGF-β2 plays an important role in inhibiting the angiogenic responses of ECs during the interaction between RPE cells and ECs and that angiogenic responses of ECs may be amplified by a decrease in TGF-β2 expression in RPE cells under pathologic conditions.

Experimental Models in Neovascular Age Related Macular Degeneration

“…Indeed, RPE cells decreased the levels of VEGFR2 in HuVEC and inhibited their migration. This result suggests that angiogenic responses of endothelial cells is amplified by a decrease in TGF-β2 expression in RPE cells under pathologic conditions[ 32 ].…”

Determination of Vascular Endothelial Growth Factor-B Concentrations in Aqueous Humor and Plasma of Neovascular Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy Patients Before and After Anti-VEGF Therapy

“…In patients with PCV, VEGF-B baseline levels decreased to 4.11 ± 5.46 ng/mL after the 1st IVR but returned to the baseline levels, 5.36 ± 6.94 ng/mL after the 2nd IVR (all P [ 0.05). VEGF vascular endothelial growth factor, BL baseline, 1st IVR first intravitreal injection ranibizumab, 2nd IVR second intravitreal injection ranibizumab, nAMD neovascular age-related macular degeneration, PCV polypoidal choroidal angiopathy elucidated to have a key role in angiogenesis and permeability [18,19]. Therefore, the relationships between VEGF-B and coactions with the VEGFR1 and VEGFR2 receptors is fairly intricate and it resulted in VEGF-B becoming the most elusive cytokine of the VEGF family, because its functions in the eye remained to be fully elucidated.…”