RESUMO
VEGF-induced neovascularization plays a pivotal role in corneal neovascularization (CoNV). The current study investigated the potential effect of ginsenoside Rh2 (GRh2) on neovascularization. In HUVECs, pretreatment with GRh2 largely attenuated VEGF-induced cell proliferation, migration, and vessel-like tube formation in vitro. At the molecular level, GRh2 disrupted VEGF-induced VEGF receptor 2 (VEGFR2)-Grb-2-associated binder 1 (Gab1) association in HUVECs, causing inactivation of downstream AKT and ERK signaling. Gab1 knockdown (by targeted short hairpin RNA) similarly inhibited HUVEC proliferation and migration. Notably, GRh2 was ineffective against VEGF in Gab1-silenced HUVECs. In a mouse cornea alkali burn model, GRh2 eyedrops inhibited alkali-induced neovascularization and inflammatory cell infiltrations in the cornea. Furthermore, alkali-induced corneal expression of mRNAs/long noncoding RNAs in cornea were largely attenuated by GRh2. Overall, GRh2 inhibits VEGF-induced angiogenic effect via inhibiting VEGFR2-Gab1 signaling in vitro. It also alleviates angiogenic and inflammatory responses in alkali burn-treated mouse corneas.-Zhang, X.-P., Li, K.-R., Yu, Q., Yao, M.-D., Ge, H.-M., Li, X.-M., Jiang, Q., Yao, J., Cao, C. Ginsenoside Rh2 inhibits vascular endothelial growth factor-induced corneal neovascularization.
Assuntos
Anti-Inflamatórios/farmacologia , Neovascularização da Córnea/tratamento farmacológico , Ginsenosídeos/farmacologia , Proteínas Adaptadoras de Transdução de Sinal , Animais , Anti-Inflamatórios/uso terapêutico , Córnea/efeitos dos fármacos , Córnea/metabolismo , Neovascularização da Córnea/etiologia , Neovascularização da Córnea/metabolismo , Ginsenosídeos/uso terapêutico , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/fisiologia , Humanos , Gelo , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos Endogâmicos ICR , Fosfoproteínas/metabolismo , Fator A de Crescimento do Endotélio Vascular/toxicidade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
The purpose of this study was to evaluate the effect of ethanol extract of Diospyros kaki (EEDK) leaves on corneal neovascularization (CoNV) in rats. One week after the alkali burns in the corneas, the CoNV area coverage in the CoNV-positive control group, 100 mg/kg EEDK group, and 200 mg/kg EEDK group was 43.3% ± 5.5%, 337.7% ± 2.5%, and 27.2% ± 4.3%, respectively. The areas of CoNV in the EEDK-treated groups were significantly different from those of the CoNV group. EEDK significantly attenuated the upregulation of vascular endothelial growth factor, fibroblast growth factor, interleukin-6, and matrix metalloproteinase-2 (MMP-2) protein levels. Orally administrated D. kaki inhibited CoNV development in rats.
Assuntos
Álcalis/toxicidade , Queimaduras Químicas/complicações , Neovascularização da Córnea/tratamento farmacológico , Diospyros/química , Extratos Vegetais/administração & dosagem , Animais , Neovascularização da Córnea/etiologia , Neovascularização da Córnea/genética , Neovascularização da Córnea/metabolismo , Modelos Animais de Doenças , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Ratos , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
OBJECTIVE: To evaluate the effects of topical bevacizumab and topical sunitinib on vascular microdensity and morphology of corneal neovascularization (NV). METHODS: A total of 33 rabbits were distributed into 3 groups: group 1 (control; n=11): saline; group 2 (n=11): bevacizumab 5mg/ml; and group 3 (n=11): sunitinib 0.5mg/ml. A corneal NV model was used, based on sutures in the right eye of each rabbit. Each treatment was administered topically 3 times daily for 14 days. Corneas were then processed for the study of vascular microdensity (6 eyes) and vascular morphology analysis (5 eyes) using enzymatic staining histological techniques RESULTS: The vascular response in group 3 was limited to small-sized tree formations with various vascular axes compared with the extensive, lush and directional corneal NV of group 1 and 2. In the histological sections near the limb, there were no differences in vascular microdensity studies between the three groups. However, the mean sectional area of vessels (MSAV) in group 3 was 41.88% lower than in group 1 and 19.19% lower than in group 2. In distal sections, there were no differences between groups 1 and 2. However, group 3 was characterized by absence of vessels. CONCLUSIONS: Bevacizumab produced no changes in the morphology of the vessels or the vascular microdensity. Sunitinib reduced the size of the new vessels and induced changes in the vascular tree.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Córnea/irrigação sanguínea , Neovascularização da Córnea/tratamento farmacológico , Indóis/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirróis/uso terapêutico , Inibidores da Angiogênese/farmacologia , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Artérias/efeitos dos fármacos , Artérias/ultraestrutura , Bevacizumab , Neovascularização da Córnea/etiologia , Neovascularização da Córnea/patologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Indóis/farmacologia , Masculino , Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Pirróis/farmacologia , Coelhos , Sunitinibe , Suturas/efeitos adversos , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Veias/efeitos dos fármacos , Veias/ultraestruturaRESUMO
Corneal neovascularization is a significant, sight-threatening complication of many ocular surface disorders. Various growth factors and proteinases are involved in corneal neovascularization. The data supporting a causal role for vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs) are extensive. Inhibition of VEGF and MMPs is a main strategy for treating corneal neovascularization. Several findings have shown that corneal neovascularization can be reduced by using anti-VEGF and anti-MMPs agents. Efficacy of a nutrient mixture (NM) containing lysine, proline, ascorbic acid, and green tea extract has been demonstrated for reducing VEGF and MMPs secretion by various cells. Moreover, NM can inhibit endothelial cell migration and capillary tube formation. We herein note that topical application of NM is potentially useful for inhibiting corneal neovascularization and restoration of corneal clarity. Further investigations in animal models are needed to place NM alongside corneal neovascularization therapeutics.