Hepatocyte growth factor-regulated tyrosine kinase substrate is essential for endothelial cell polarity and cerebrovascular stability

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 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. CONCLUSIONS: 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. TRANSLATIONAL PERSPECTIVE: The structural and functional integrity of cerebral vasculature is critical for supporting normal brain function. Mutations of genes that play important roles in blood vessel development cause not only cardiovascular diseases, but also neurological disorders. In this study, we discovered a novel physiological function of Hgs in the maintenance of EC polarity and cerebrovascular stability, demonstrating that endothelial ESCRT machinery has an essential role in maintaining the integrity of cerebral vasculature. This provides insights into the potential pathogenic links between ESCRT dysfunction and cardiovascular diseases, as well as neurodegenerative disorders.