Retinal vascularization is arrested at the early (hyperoxia) stage in retinopathy of prematurity (ROP), a leading cause of blindness in children. Estrogen was reported to alleviate ROP by inhibiting reactive oxygen species, the upstream signaling molecules of endoplasmic reticulum stress (ERS). Astrocytes have long been proposed to guide angiogenesis, because they form a reticular network that provides a substrate for migrating endothelial cells. However, the factors that control the vascularization of the immature retina and the therapeutic mechanism of estrogen in early ROP remain poorly understood. This study aimed to investigate the role of G‐protein‐coupled estrogen receptor (GPER), an estrogen receptor distributed in the endoplasmic reticulum (ER), in protecting retinal astrocytes under hyperoxia and the association with ERS. The results showed that GPER was widely expressed in retinal astrocytes. GPER activation increases cell viability, decreases apoptosis, and autophagy of retinal astrocytes, decreases inositol‐1,4,5‐triphosphate receptor activity, and increases Ca²⁺ concentration in ER of astrocytes under hyperoxia. GPER blockade reversed all of these changes. Together, our findings indicate that GPER can protect the survival of retinal astrocytes by inhibiting ERS under hyperoxia.

中文翻译：

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通过激活G蛋白偶联雌激素受体抑制内质网应激，保护高氧下的视网膜星形胶质细胞

视网膜血管形成在早产儿视网膜病变（ROP）的早期（高氧血症）阶段被阻止，ROP是儿童失明的主要原因。据报道，雌激素可通过抑制活性氧（内质网应激（ERS）的上游信号分子）来减轻ROP。长期以来一直提出星形胶质细胞来指导血管生成，因为它们形成网状网络，为网状内皮细胞的迁移提供了底物。然而，早期R​​OP中控制未成熟视网膜血管形成的因素和雌激素的治疗​​机制仍然知之甚少。这项研究旨在研究G蛋白偶联雌激素受体（GPER）（一种分布于内质网（ER）中的雌激素受体）在高氧下保护视网膜星形胶质细胞以及与ERS的关系中的作用。结果表明，GPER在视网膜星形胶质细胞中广泛表达。GPER激活可增加细胞活力，减少视网膜星形胶质细胞的凋亡和自噬，降低肌醇-1,4,5-三磷酸受体活性并增加钙高氧下星形胶质细胞ER中的²⁺浓度。GPER封锁扭转了所有这些变化。总之，我们的发现表明，GPER可以通过抑制高氧下的ERS来保护视网膜星形胶质细胞的存活。