{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T13:46:07Z","timestamp":1791899167051,"version":"4.3.4"},"reference-count":88,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Stroke"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Leptomeningeal collaterals form a critical vascular network that enlarges to support retrograde reperfusion after ischemic stroke, yet the cellular mechanisms governing their structural plasticity remain poorly defined. Here we identify an immune-responsive vascular niche and uncover a central role for bone marrow\u2013derived monocytes in regulating collateral remodeling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      GFP (green fluorescent protein)\n                      <jats:sup>+<\/jats:sup>\n                      bone marrow chimeric mice and inducible monocyte-specific\n                      <jats:italic toggle=\"yes\">Ccr2-CreERT2<\/jats:italic>\n                      (C-C chemokine receptor 2 promoter-driven tamoxifen-inducible Cre recombinase\u2013estrogen receptor T2)\n                      <jats:italic toggle=\"yes\">\/EphA4<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">f<\/jats:italic>\n                      <\/jats:sup>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">\/f<\/jats:italic>\n                      <\/jats:sup>\n                      and\n                      <jats:italic toggle=\"yes\">Ccr2-CreERT2\/EphA4<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">f\/f<\/jats:italic>\n                      <\/jats:sup>\n                      <jats:italic toggle=\"yes\">\/Tie2<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">f\/f<\/jats:italic>\n                      <\/jats:sup>\n                      (tyrosine kinase with immunoglobulin-like and EGF-like domains 2) mice underwent permanent middle cerebral artery occlusion to assess monocyte recruitment, collateral remodeling, cerebral blood flow, infarct volume, and functional recovery. Mechanistic studies evaluated EphA4 (ephrin receptor A4)\/Tie2-PI3K (phosphatidylinositol 3-kinase) \u03b1 signaling in macrophages, while serum sTie2 (soluble Tie2) levels and immune transcriptomic profiles were analyzed in patients with acute large vessel occlusion and correlated with angiographic collateral grade.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      We observed rapid recruitment of EphA4-expressing monocytes to pial collateral vessels after permanent middle cerebral artery occlusion. EphA4 knockout chimeric mice show a marked increase in monocyte recruitment, enhanced collateral diameters, improved cerebral blood flow, reduced infarct volume, and accelerated motor recovery. EphA4-null macrophages exhibited elevated Tie2, p-Akt (phosphorylated protein kinase B), and PI3K\u03b1, a phenotype reversed by PI3K\u03b1 inhibition or sTie2. We further show enhanced permanent middle cerebral artery occlusion\u2013induced collateral enlargement, neuroprotection, and monocyte recruitment using\n                      <jats:italic toggle=\"yes\">Ccr2-Cre<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">ERT2<\/jats:italic>\n                      <\/jats:sup>\n                      <jats:italic toggle=\"yes\">\/EphA4<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">f\/f<\/jats:italic>\n                      <\/jats:sup>\n                      mice, which is attenuated in\n                      <jats:italic toggle=\"yes\">Ccr2-Cre<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">ERT2<\/jats:italic>\n                      <\/jats:sup>\n                      <jats:italic toggle=\"yes\">\/EphA4<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">f\/f<\/jats:italic>\n                      <\/jats:sup>\n                      <jats:italic toggle=\"yes\">\/Tie2<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">f\/f<\/jats:italic>\n                      <\/jats:sup>\n                      double-knockout mice. Notably, we find that serum sTie2 levels are elevated in human patients with large vessel occlusion, and these levels correlate with improved digital subtraction angiography collateral scoring and key immune-specific bulk transcriptomic changes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Together, these findings establish immune cell\u2013intrinsic EphA4\/Tie2 signaling as a key regulator of leptomeningeal collateral enlargement and reveal a therapeutic axis for augmenting perfusion after stroke.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/strokeaha.126.056479","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T09:00:11Z","timestamp":1784883611000},"page":"3134-3151","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Leptomeningeal Collaterals Constitute an Immune-Responsive Vascular Niche in Ischemic Stroke"],"prefix":"10.1161","volume":"57","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1901-6980","authenticated-orcid":true,"given":"Jing","family":"Ju","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg (J.J., K.S., C.d.J., T.S., M.H.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-3817-0803","authenticated-orcid":true,"given":"Kylee","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg (J.J., K.S., C.d.J., T.S., M.H.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-6047-7614","authenticated-orcid":true,"given":"Collin E.","family":"Tanchanco","sequence":"additional","affiliation":[{"name":"Section of Neurointerventional Surgery and Virginia Tech Carilion School of Medicine, Virginia Tech, Roanoke (C.E.T., B.M.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2714-5886","authenticated-orcid":true,"given":"Caroline","family":"de Jager","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg (J.J., K.S., C.d.J., T.S., M.H.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-9244-5336","authenticated-orcid":true,"given":"Thinna","family":"Svetanant","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg (J.J., K.S., C.d.J., T.S., M.H.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2830-954X","authenticated-orcid":true,"given":"Biraj M.","family":"Patel","sequence":"additional","affiliation":[{"name":"Section of Neurointerventional Surgery and 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