ENDOTHELIAL PROX1 INDUCES BLOOD-BRAIN BARRIER DISRUPTION IN THE CENTRAL NERVOUS SYSTEM

Area of Science:

• Neuroscience
• Vascular Biology
• Cell Biology

Background:

• The central nervous system (CNS) parenchyma was traditionally considered devoid of lymphatic vasculature.
• Ectopic expression of lymphatic endothelial cell (LEC) markers, like Prospero Homeobox 1 (PROX1), is observed in brain tumors and malformations.
• This suggests a potential role for LEC markers in cerebrovascular abnormalities and blood-brain barrier (BBB) dysfunction.

Purpose of the Study:

• To investigate the role of ectopic LEC properties in BBB disruption.
• To explore the impact of endothelial PROX1 overexpression on CNS vascular development and BBB integrity.

Main Methods:

• Utilized endothelial cell-specific Prox1 overexpression mutants in mice.
• Induced Prox1 overexpression during embryonic and postnatal stages of BBB development and maturation.
• Analyzed vascular malformations, vascular leakage, and BBB disruption.
• Assessed the expression of BBB-associated genes, including ß-catenin and Claudin-5.

Main Results:

• Embryonic induction of endothelial Prox1 overexpression resulted in hybrid blood-lymphatic phenotypes in CNS vasculature.
• Postnatal Prox1 overexpression did not yield the same hybrid phenotypes but still caused BBB disruption.
• Ectopic Prox1 expression led to significant vascular malformations and enhanced leakage, disrupting the BBB.
• PROX1 was found to downregulate key BBB-associated genes, compromising BBB integrity and Wnt/ß-catenin signaling.

Conclusions:

• Endothelial PROX1 expression can induce abnormal CNS vascular phenotypes and BBB disruption.
• PROX1 negatively regulates essential BBB components, impacting BBB development and maintenance.
• These findings shed light on the mechanisms underlying BBB abnormalities in certain neurological conditions.