2026/01/01 by Sara González-Hernández, Ryo Sato, Yuya Sato +7 · 1 voice
Medicine · Neuroscience · #Cerebrospinal fluid and hydrocephalus #Lymphatic System and Diseases #Vascular Malformations and Hemangiomas
paper · doi:10.1172/jci.insight.187716
openalex created_date 2026/01/01 · openalex publication_date 2026/01/01 · openalex updated_date 2026/07/21
The central nervous system (CNS) parenchyma has conventionally been believed to lack lymphatic vasculature, likely owing to a non-permissive microenvironment that hinders the formation and growth of lymphatic endothelial cells (LECs). Recent findings of ectopic expression of LEC markers including prospero homeobox 1 (PROX1), a master regulator of lymphatic differentiation, and the vascular permeability marker plasmalemma vesicle-associated protein (PLVAP) in certain glioblastomas (GBM) and brain arteriovenous malformations have prompted investigation into their roles in cerebrovascular malformations, tumor environments, and blood-brain barrier (BBB) abnormalities. To explore the relationship between ectopic LEC properties and BBB disruption, we used endothelial cell-specific Prox1 overexpression mutants. When induced during embryonic stages of BBB formation, endothelial Prox1 expression induces hybrid blood-lymphatic phenotypes in the developing CNS vasculature. This effect is not observed when Prox1 is overexpressed during postnatal BBB maturation. Ectopic Prox1 expression leads to significant vascular malformations and enhanced vascular leakage, resulting in BBB disruption when induced during both embryonic and postnatal stages. Mechanistically, PROX1 downregulates critical BBB-associated genes, including β-catenin and claudin-5, which are essential for BBB development and maintenance. These findings suggest that PROX1 compromises BBB integrity by negatively regulating BBB-associated gene expression and Wnt/β-catenin signaling.