Sorenson Christine M, Wang Shoujian, Darjatmoko Soesiawati R, Gurel Zafer, Liu Bo, Sheibani Nader
Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States.
McPherson Eye Research Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States.
Front Cell Dev Biol. 2021 Apr 21;9:671989. doi: 10.3389/fcell.2021.671989. eCollection 2021.
Tight regulation of positive and negative regulators of angiogenesis is essential, particularly in the eye where their dysregulation can lead to vision loss. Thrombospondin-1 (TSP1) is a matricellular protein that negatively regulates angiogenesis and inflammation in the eye. It aids ocular vascular homeostasis such that its loss contributes to increased retinal vascular density and pathologic ocular neovascularization. Our previous studies demonstrated that mice globally lacking TSP1 expression had increased retinal vascular density, decreased hyperoxia-induced retinal vessel loss, and increased choroidal neovascularization. Here we determined the impact to the ocular vasculature of endothelial cell, pericyte, or astrocyte loss of TSP1 expression. Only lack of TSP1 expression in endothelial cells was sufficient to increase choroidal neovascularization with mice lacking expression in pericytes or astrocytes not demonstrating a significant impact. Although the global TSP1 knockout mice demonstrated increased retinal vascular density, individual cell type loss of TSP1 resulted in decreased retinal endothelial cell numbers before and/or after vascular maturation in a cell type specific fashion. Retinas from mice lacking TSP1 expression in endothelial cells, pericytes or astrocytes were not protected from retinal vessel regression in response to hyperoxia as we previously observed in the global knockout. Thus, modulation of TSP1 expression in individual cell types demonstrates a response that is unique to the role TSP1 plays in that cell type of interest, and their coordinated activity is critical for vision.
严格调控血管生成的正负调节因子至关重要，尤其是在眼睛中，因为它们的失调会导致视力丧失。血小板反应蛋白-1（TSP1）是一种基质细胞蛋白，对眼睛中的血管生成和炎症起负调节作用。它有助于维持眼部血管稳态，其缺失会导致视网膜血管密度增加和病理性眼部新生血管形成。我们之前的研究表明，全球范围内缺乏TSP1表达的小鼠视网膜血管密度增加，高氧诱导的视网膜血管损失减少，脉络膜新生血管形成增加。在这里，我们确定了内皮细胞、周细胞或星形胶质细胞中TSP1表达缺失对眼部血管系统的影响。只有内皮细胞中缺乏TSP1表达足以增加脉络膜新生血管形成，而周细胞或星形胶质细胞中缺乏表达的小鼠未表现出显著影响。尽管全球TSP1基因敲除小鼠的视网膜血管密度增加，但TSP1在单个细胞类型中的缺失会以细胞类型特异性方式导致血管成熟前后视网膜内皮细胞数量减少。正如我们之前在全球基因敲除小鼠中观察到的那样，内皮细胞、周细胞或星形胶质细胞中缺乏TSP1表达的小鼠视网膜并不能免受高氧引起的视网膜血管消退的影响。因此，调节单个细胞类型中TSP1的表达显示出一种对TSP1在该特定细胞类型中所起作用而言独特的反应，并且它们的协同活动对视力至关重要。
