Inhibition of proprotein convertase SKI-1 prevents blood vessel alteration after stroke.

ABSTRACT: Neutralizing factors involved in blood vessel dysfunction offer a promising strategy for stroke recovery. Many extracellular proteins need enzymatic activation to function, and blocking this activation is an untapped approach to restoring vessel integrity. Here we demonstrate that inhibition of the extracellular protease SKI-1 with PF-429242 restores blood vessel integrity and promotes functional recovery in both large and small animal models for stroke. Single-cell mRNA sequencing identified molecular signatures suggesting that PF-429242 restores the expression of genes involved in vessel integrity in endothelial cells. Moreover, we identify a mechanism whereby RGMa cleavage by SKI-1 is required for RGMa to interact with Neogenin and alter vessel integrity. Either preventing RGMa cleavage

SUBMITTER: Shabanzadeh AP 

PROVIDER: S-EPMC12436164 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature