An atlas of cGAS-STING signaling in pathophysiological angiogenesis and retinal vascular homeostasis across species.

Abnormal angiogenesis is the leading cause of vision loss globally, but current anti-angiogenic treatments are unsatisfactory and incompetent. Thus, novel therapies targeting angiogenesis are urgently needed. Previously, we revealed a positive association between cGAS-STING signaling and angiogenic factors in the mouse model with ischemic retinopathy. However, whether cGAS-STING signaling regulates retinal angiogenesis remained largely unknown. Here, we analyzed single-cell RNA sequencing databases from the epiretinal fibrovascular membranes, developing mouse retinas, and normal adult retinas from Homo sapiens, Sus scrofa, and Macaca. Notably, we observed spatially and temporally identical expression patterns of cGAS-STING signaling and angiogenesis. In particular, cGAS-STING signaling showed the strongest correlation with angiogenesis in retinal endothelia from mice at postnatal days 3 and 6. Endothelia-specific knockout of Sting 1 in mice retarded retinal vascular growth, which was due to attenuation of VEGFA-VEGFR2 signaling as suggested by bulk RNA sequencing. In human retinal vascular endothelial cells, deletion of STING1 prohibited VEGFR2 activation, down-regulated the levels of endothelial markers, and compromised endothelial proliferation and migration, which were counteracted by overexpression of STING1. This study demonstrated an evolutionally conserved interaction between cGAS-STING signaling and VEGFA-VEGFR2 signaling in pathophysiological angiogenesis and vascular homeostasis, thus providing a novel therapeutic target for treating retinal vascular diseases.