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bioRxiv · 10.1101/2025.04.11.648449

Vascular endothelial-specific loss of TGF-beta signaling as a model for choroidal neovascularization and central nervous system vascular inflammation

Wang, Y.·Rattner, A.·Li, Z.·Smallwood, P. M.·Nathans, J.
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Abstract

In mice, postnatal endothelial cell (EC)-specific knockout of the genes coding for Transforming Growth Factor-Beta Receptor (TGFBR)1 and/or TGFBR2 eliminates TGF-beta signaling in vascular ECs and leads to distinctive central nervous system (CNS) vascular phenotypes. Knockout mice exhibit (1) reduced intra-retinal vascularization, (2) choroidal neovascularization with occasional anastomoses connecting choroidal and intraretinal vasculatures, (3) infiltration of diverse immune cells into the retina, including macrophages, T-cells, B-cells, NK cells, and dendritic cells, (4) a close physical association between immune cells and retinal vasculature, (5) a pro-inflammatory transcriptional state in CNS ECs, with increased ICAM1 immunoreactivity, and (6) increased Smooth Muscle Actin immunostaining in CNS pericytes. Comparisons of the retinal phenotype with two other genetic models of retinal hypovascularization - loss of Norrin/Fzd4 signaling and loss of VEGF signaling - shows that the immune cell infiltrate is greatest with loss of TGF-beta signaling, more modest with loss of Norrin/Fzd4 signaling, and undetectable with loss of VEGF signaling. The phenotypes caused by loss of TGF-beta signaling in ECs recapitulate some of the cardinal features of retinal and neurologic diseases associated with vascular inflammation. These observations suggest that therapies that promote TGF-beta-dependent anti-inflammatory responses in ECs could represent a promising strategy for disease modulation.

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Wang, Y., Rattner, A., Li, Z., Smallwood, P. M., Nathans, J.. 2025-04-11. Vascular endothelial-specific loss of TGF-beta signaling as a model for choroidal neovascularization and central nervous system vascular inflammation. https://doi.org/10.1101/2025.04.11.648449

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