{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T19:46:36Z","timestamp":1775936796679,"version":"3.50.1"},"posted":{"date-parts":[[2025,3,6]]},"group-title":"Neuroscience","reference-count":30,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,3,6]],"date-time":"2025-03-06T00:00:00Z","timestamp":1741219200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,3,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Leptomeningeal collaterals are distal pial arterial anastomotic vessels that provide an alternative route for redistributing cerebral blood flow following arterial obstruction, thereby limiting tissue damage. However, the regulatory mechanisms and strategies to enhance this adaptive response remain under investigation. This study explored the pharmacological effects of Tie2 receptor activation, using the peptide agonist Vasculotide, following permanent middle cerebral artery occlusion (pMCAO). Vasculotide improved collateral growth and remodeling, which correlated with reduced infarct volume, enhanced blood flow, and functional recovery within 24hrs post-pMCAO. In contrast, collateral growth was attenuated in Tie2 and EphA4\/Tie2 double knockdown mice, while the loss of EphA4 increased Tie2 and Ang-1 expression and mimicked the positive effects of Vasculotide following stroke. Furthermore, bulk RNA sequencing of meningeal tissue identified key transcriptomic changes, including alterations in AJ-associated transcripts, such as\n                  <jats:italic>Krt5<\/jats:italic>\n                  ,\n                  <jats:italic>Krt14<\/jats:italic>\n                  , and\n                  <jats:italic>Col17a1<\/jats:italic>\n                  , in the ipsilateral meninges of both endothelial cell-specific EphA4 knockout and Vasculotide-treated mice. Krt5 expression was found upregulated on meningeal arterial vascular network in injured KO mice, highlighting a potential new mediator of meningeal vascular remodeling. These findings illustrate that EphA4 and Tie2 play opposing roles in collateral remodeling, including the regulation of Krt5. Modulating their activity could potentially enhance the collateral response to stroke.\n                <\/jats:p>","DOI":"10.1101\/2025.02.28.640890","type":"posted-content","created":{"date-parts":[[2025,3,7]],"date-time":"2025-03-07T07:39:31Z","timestamp":1741333171000},"source":"Crossref","is-referenced-by-count":0,"title":["Tie2-Dependent Mechanisms Promote Leptomeningeal Collateral Remodeling and Reperfusion Following Stroke"],"prefix":"10.64898","author":[{"given":"Alexandra M.","family":"Kaloss","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, VA 24061, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caroline","family":"de Jager","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, VA 24061, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kennedie","family":"Lyles","sequence":"additional","affiliation":[{"name":"School of Neuroscience, Virginia Tech, Blacksburg VA 24061, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nathalie A.","family":"Groot","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, VA 24061, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jackie","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Virginia Tech, Blacksburg, VA 24061, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Lin","sequence":"additional","affiliation":[{"name":"Genetics, Bioinformatics and Computational Biology Program, Blacksburg, VA 24061, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hehuang","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, VA 24061, USA"},{"name":"Genetics, Bioinformatics and Computational Biology Program, Blacksburg, VA 24061, USA"},{"name":"Center for Engineered Health, VT, Blacksburg, Virginia, 24061, USA,"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John B.","family":"Matson","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Virginia Tech, Blacksburg, VA 24061, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michelle H.","family":"Theus","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, VA 24061, USA"},{"name":"Center for Engineered Health, VT, Blacksburg, Virginia, 24061, USA,"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026041112272443000_2025.02.28.640890v1.1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000004858"},{"key":"2026041112272443000_2025.02.28.640890v1.2","doi-asserted-by":"publisher","DOI":"10.1007\/s00062-019-00858-1"},{"key":"2026041112272443000_2025.02.28.640890v1.3","doi-asserted-by":"crossref","unstructured":"Zhang, H. , D. 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