Notch1 induces endothelial plasticity to mediate hyaloid vessel involution

Hyaloid vascular regression is a critical developmental process essential for vitreous transparency and normal vision, yet the molecular cues orchestrating its involution remain incompletely defined. Here, we identify Notch1 as a pivotal regulator of hyaloid vessel clearance, acting independently of apoptosis to coordinate endothelial detachment, transient plasticity, and migration. Using an endothelial-specific Notch1 knockout mouse model, we demonstrate that loss of Notch1 results in persistent hyaloid vasculature characterized by excessive proliferation and stabilization of the vascular network. Mechanistically, Notch1 activation during the regression window induces endothelial-to-mesenchymal transition (EndoMT) marked by Snail1 and Slug upregulation. This transcriptional signature is accompanied by detachment of endothelial cells from the vascular tubes. In contrast, Notch1-deficient hyaloid vessels retain endothelial cells stably adherent to the vessel wall. Further analysis reveals that Wnt receptors FZD4, LRP5 and LRP6 previously implicated in hyaloid involution are transcriptionally downregulated in Notch1-deficient hyaloids, suggesting that the collaboration between these processes may occur through crosstalk between the Notch and Wnt pathways. Collectively, our findings uncover a Notch1-driven multicellular regression program that governs developmental vessel regression, redefining the molecular principles of vascular pruning. These results have broad implications for understanding vascular remodeling in both physiological and pathological contexts and may guide therapeutic strategies to modulate vascular regression in ocular disorders. One-Sentence SummaryNotch1 drives hyaloid regression through a multicellular program that defines an apoptosis-non-exclusive paradigm of vessel pruning.