AIMS: Hepatocyte growth factor-regulated tyrosine kinase substrate (Hgs), a key 
component of the endosomal sorting complex required for transport (ESCRT), has 
been implicated in many essential biological processes. However, the 
physiological role of endogenous Hgs in the vascular system has not previously 
been explored. Here, we have generated brain endothelial cell (EC) specific Hgs 
knockout mice to uncover the function of Hgs in EC polarity and cerebrovascular 
stability.
METHODS AND RESULTS: Knockout of Hgs in brain ECs led to impaired endothelial 
apicobasal polarity and brain vessel collapse in mice. We determined that Hgs is 
essential for recycling of vascular endothelial (VE)-cadherin to the plasma 
membrane, since loss of Hgs blocked trafficking of endocytosed VE-cadherin from 
early endosomes to recycling endosomes, and impaired the motility of recycling 
endosomes. Supportively, overexpression of the motor kinesin family member 13A 
(KIF13A) restored endosomal recycling and rescued abrogated polarized 
trafficking and distribution of VE-cadherin in Hgs knockdown ECs.
CONCLUSION: These data uncover a novel physiological function of Hgs and support 
an essential role for the ESCRT machinery in the maintenance of EC polarity and 
cerebrovascular stability.