Résumé
As resident immune cells of the retina, retinal microglia constantly monitor the changes of their surroundings and maintain homeostasis through signal transduction with other retinal cells. Retinal microglia play a crucial role not only in the development and physiological processes of the retinal vascular system, but also in pathological neovascularization. In certain retinopathies, activated microglia can stimulate abnormal angiogenesis through neurovascular coupling, leading to irreversible damage. However, the exact mechanisms underlying this process are still unclear. In this review, a brief overview of the relationship between microglia and retinal neovascularization was provided, and the involved cellular and molecular signaling mechanisms were reviewed, aiming to offer new and effective strategies for the prevention and treatment of retinal neovascularization diseases.
Résumé
Objective To investigate the mechanisms of quercetin in retinal angiogenesis via in vitro and in vivo studies.Methods Human umbilical vein endothelial cells (HUVECs) was used in in vitro study,and oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV) animal models were used in in vivo study.In the in vitro cell study,normal control group,VEGF-165 treatment group and VEGF-165 combined with quercetin treatment group were used.Cell counting kit-8 (CCK8) and Transwell were used to measure HUVECs cell viability,including proliferation and migration.OIR and CNV animal models were administrated through intraperitoneal injection of quercetin,and the non-perfusion area and CNV aera were evaluated.Western blot assay was used to detect the expression of integrin α5 and integrin β3 expression.In the animal study,18 breastfeeding mice and 18 infant mice were randomly divided into normal control group,model control group and quercetin treatment group,6 for each group.The animal feeding and use was in accordance with the standards set by the ARVO,and the experiment was approved by the Ethic Committee for Experimental Animal of Fu Xing Hospital,Capital Medical University (2016-KY-0036).Results In the in vitro study,VEGF-165 (20 ng/ml) promoted the proliferation and migration of HUVECs,while quercetin (50 μmol/L) inhibited HUVECs proliferation and migration significantly,comparing to the VEGF-165 treatment group (proliferation:Fgroups =18.51,P =0.00;migration:F =85.74,P =0.00).In the in vivo studies,quercetin 20 mg/(kg·day) decreased the non-perfusion area and CNV area comparing to the untreated groups,with significant differences between them (t =6.02,P =0.00;t =5.79,P =0.00).Besides,quercetin down-regulated the expression of integrin α5 and integrin β3 significantly both in the in vitro and in vivo studies.Western blot test showed that integrin α5 and integrin β3 in VEGF-165+quercetin processing 24 hours group were significantly decreased than those in the VEGF-165 group,with significant differences between them (t =4.46,P＜0.05;t =5.18,P＜0.01).Compared with the VEGF-165 +quercetin 24 hours group,the integrin α5 and integrin β3 in VEGF-165 +quercetin processing 48 hours group were increased,but they were still significantly increased than those in the VEGF-165 group,with significant differences between them (t =6.54,P ＜ 0.05;t =7.17,P ＜ 0.01).For the animal studies,quercetin also inhibited the levels of integrin α5 and integrin β3 in OIR and CNV models (t =5.44,13.52;both at P=0.00).Conclusions Quercetin can inhibit the retinal and choroidal neovascularization through integrin pathway,which provides a new treatment strategy for clinical therapy.
Résumé
Being regarded as one kind of specialized tissue macrophages in central nervous system,microglia plays a key role in maintenance of retinal integrity and function.However,recent investigations have revealed that microglia has migrated in the brain before the vascular network formation.Besides their role of immunological modulation in inflammation response,it also has strong effects on shaping vasculature during development and remolding vessels in pathological processes.Microglia contact with the angiogenic vessel,promoting the anastomoses of sprouts.Interestingly,reciprocal interactions between microglia and endothelial cells have been a hot topic.Secreted exosomes can offer a vehicle for the exchange of information between cells engaged in angiogenesis.Notch signaling also plays an important role in cell-to-cell communication during angiogenesis.The participation of microglia in retinal blood vessel formation has received little attention to date.Additional basic studies may ultimately clarify the significance of this cell and provide valuable therapeutic insight into treatment for retinal pathological neovascularization.In this review,we focued on the origin of microglia and summarize how the crosstalk between microglia and endothelial cells modulate the physical development of vessel and angiogenesis.