SOX9 Protein Identified as Key Regulator of Brain and Retinal Blood Vessel Formation
Researchers have identified the transcription factor SOX9 as a critical regulator of endothelial tip cells, the specialized cells that guide new blood vessel formation in the developing brain and retina. Mouse studies showed that deleting SOX9 in endothelial cells impaired vascularization of the brain and neuroretina, while overexpressing it enhanced sprouting behavior. The findings also reveal that post-stroke angiogenesis lacks SOX9 activity, suggesting a potential therapeutic target for improving vascular regeneration after brain injury.
A new preprint study published on bioRxiv used endothelial-specific SOX9 knockout mice combined with single-cell, spatial, and bulk RNA sequencing to investigate how blood vessels grow into the brain and retina during development. The researchers found that SOX9 is selectively enriched in endothelial tip cells — the leading cells of angiogenic sprouts — specifically in neural tissues. Loss of SOX9 in endothelial cells disrupted the tip cell transcriptomic program, reducing sprouting angiogenesis and matrix-remodeling activity, while SOX9 overexpression in human umbilical vein endothelial cells (HUVECs) promoted neural tip cell-like gene signatures and enhanced invasion and sprouting in functional assays. The study also examined ischemic stroke, finding that a transient angiogenic endothelial population does emerge in the ischemic zone but fails to express SOX9 and lacks key features of developmental brain tip cells. This distinction between developmental and injury-induced vascular responses suggests that the brain's natural repair mechanisms after stroke are fundamentally incomplete. The authors propose SOX9 as a potential therapeutic target to promote more effective vascular regeneration following ischemic brain injury.
What's missing
As a preprint, this work has not yet undergone formal peer review. The study's own scope leaves open whether SOX9 manipulation in adult or post-stroke models can safely and effectively restore functional vasculature without off-target effects, and whether findings in mice will translate to human cerebrovascular biology. The mechanisms by which SOX9 is suppressed during injury-induced angiogenesis — and whether that suppression is reversible — are not fully characterized.
What different sources said
- bioRxivCenter
SOX9 regulates endothelial tip cell specification to promote cerebral and neuroretinal vascularization
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