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<p>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 after stroke. This work identifies a much-needed therapeutic strategy that restores blood vessel integrity and functionality, showing efficacy in large and small animals.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年8月26日

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  • Alireza P. Shabanzadeh,
  • Dene Ringuette,
  • Michal Syonov,
  • Qisi Wu,
  • Nardos G. Tassew,
  • Eric K. Mun,
  • Autumn Meek,
  • Starlee Lively,
  • Samuel E. Suntharalingham,
  • Mia Mojica,
  • Leonardo Olijnyk,
  • Beiping Qiang,
  • Warren D. Foltz,
  • Mark Reed,
  • Ignace Moya,
  • Carla Brown,
  • Jinzhou Feng,
  • Xinyue Qin,
  • Pavan Sudheer Akula,
  • Thomas Wälchli,
  • Peter L. Carlen,
  • Paula Alcaide-Leon,
  • Philippe P. Monnier

摘要

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 after stroke. This work identifies a much-needed therapeutic strategy that restores blood vessel integrity and functionality, showing efficacy in large and small animals.