Inhibition of proprotein convertase SKI-1 prevents blood vessel alteration after 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 after stroke. This work identifies a much-needed therapeutic strategy that restores blood vessel integrity and functionality, showing efficacy in large and small animals.
Authors
- C. Hendricks Brown (ORCID: https://orcid.org/0000-0002-0294-2419)
- Thomas Wälchli (ORCID: https://orcid.org/0000-0002-8961-6551)
- Qisi Wu (ORCID: https://orcid.org/0000-0003-1579-5494)
- Nardos G. Tassew (ORCID: https://orcid.org/0000-0001-9225-2579)
- Philippe P. Monnier (ORCID: https://orcid.org/0000-0002-6221-4130)
- Jinzhou Feng (ORCID: https://orcid.org/0000-0003-4987-6313)
- Mark A. Reed (ORCID: https://orcid.org/0000-0002-0293-2691)
- Dene Ringuette (ORCID: https://orcid.org/0000-0003-4567-8109)
- Peter L. Carlen (ORCID: https://orcid.org/0000-0002-3339-8102)
- Paula Alcaide‐Leon (ORCID: https://orcid.org/0000-0001-6146-7972)
- Alireza P. Shabanzadeh (ORCID: https://orcid.org/0000-0003-3585-7912)
- Warren D. Foltz (ORCID: https://orcid.org/0000-0002-2553-9083)
- Beiping Qiang (ORCID: https://orcid.org/0000-0003-2482-3354)
- Eunji Mun (ORCID: https://orcid.org/0009-0008-8590-1057)
- Michal Syonov (ORCID: https://orcid.org/0009-0009-0896-2347)
- Starlee Lively (ORCID: https://orcid.org/0000-0003-0655-535X)
- Autumn Meek (ORCID: https://orcid.org/0000-0002-6902-4620)
- Samuel Suntharalingham
- Leonardo Olijnyk
- I. Moya
- Xinyue Qin (ORCID: https://orcid.org/0000-0002-4996-499X)
- Mia Mojica
- Pavan Sudheer Akula
Institutions
- University Health Network (CA)
- University College London Hospitals NHS Foundation Trust (GB)
- University of Toronto (CA)
- Toronto Western Hospital (CA)
- Toronto Rehabilitation Institute (CA)
- The Affiliated Yongchuan Hospital of Chongqing Medical University (CN)
- Ontario Brain Institute (CA)
- Krembil Research Institute
- University College London (GB)
- Stem Cell Network (CA)
- Chongqing Medical University (CN)
Publication Details
- Journal
- Nature Cardiovascular Research
- Published
- 2025-08-26
- DOI
- https://doi.org/10.1038/s44161-025-00691-5
- Citations
- 2
- Primary Topic
- Barrier Structure and Function Studies
- Type
- article
- Field-Weighted Citation Impact
- 1.68
Funders
- Heart and Stroke Foundation of Canada