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

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 or deleting Neogenin on endothelial cells reduced blood vessel dysfunction, increased tissue preservation, and restored brain function following stroke. This work identifies a much-needed therapeutic strategy which restores blood vessel integrity and functionality, showing efficacy in small- and large-animals.