{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T07:28:16Z","timestamp":1786433296628,"version":"build-2736575974"},"reference-count":0,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T00:00:00Z","timestamp":1786406400000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Limited therapies exist to preserve tissue function in ischemia-reperfusion injury, particularly for ischemic stroke, where intravenous thrombolysis remains a primary but risky treatment option. During stroke reperfusion, mechanical forces including hemodynamic shear stress and tissue stiffness change rapidly. However, how the neurovascular endothelium senses and responds to these physical cues to drive pathological injury remains unclear.<\/jats:p>\n                  <jats:p>Using a transient middle cerebral artery occlusion and reperfusion mouse model, we mapped acute shear stress and stiffness remodeling via near-infrared II imaging and atomic force microscopy. In vivo fiber photometry, single-cell transcriptomics, electron microscopy, biochemical assays and cell-type-specific conditional knockout mice were utilized to decode the Piezo1-dependent mechanochemical signaling.<\/jats:p>\n                  <jats:p>Reperfusion-induced disturbed blood flow and aberrant tissue stiffening robustly over-activated the mechanosensitive channel Piezo1 specifically in vascular endothelial cells. Although Piezo1 was broadly detected in glial cells, genetic ablation of Piezo1 exclusively in endothelial cells, but not in astrocytes or microglia, significantly reduced infarct volume and improved neurological deficits. Mechanistically, endothelial Piezo1 hyperactivation induced adenylyl cyclase 1, driving a surge in intracellular cyclic AMP (cAMP). This triggered the assembly and release of cAMP-enriched extracellular microvesicles, which preferentially accumulated within adjacent perivascular astrocytes. The vesicular cAMP payload subsequently activated the downstream effector Epac1, dictating a spatially restricted wave of astrocyte apoptosis. Concordantly, astrocyte-specific genetic ablation of Epac1 replicated the neuroprotective phenotype, significantly alleviating ischemic brain injury.<\/jats:p>\n                  <jats:p>These findings delineate a pathogenic mechanochemical cascade at the neurovascular interface, establishing that endothelial Piezo1 translates post-ischemic mechanical stress into an apoptotic chemical signal via microvesicular cAMP-Epac1 communication. Targeting the upstream endothelial Piezo1 mechanosensor or the downstream astrocytic Epac1 effector offers a promising therapeutic strategy to preserve neurovascular unit integrity following stroke reperfusion.<\/jats:p>","DOI":"10.1093\/brain\/awag276","type":"journal-article","created":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T11:54:50Z","timestamp":1786190090000},"source":"Crossref","is-referenced-by-count":0,"title":["Mechanochemical endothelial-astrocyte signalling via Piezo1-Epac1 drives neurovascular injury after stroke"],"prefix":"10.1093","author":[{"given":"Yifei","family":"Liu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica , Shanghai ,","place":["China"]},{"name":"University of Chinese Academy of Sciences , Beijing ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Sun","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Nanjing University of Chinese Medicine , Nanjing ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maoqia","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Zhujiang Hospital of Southern Medical University , Guangzhou ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingliang","family":"Yang","sequence":"additional","affiliation":[{"name":"Icahn School of Medicine at Mount Sinai , New York ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zizhen","family":"Sheng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica , Shanghai ,","place":["China"]},{"name":"University of Chinese Academy of Sciences , Beijing ,","place":["China"]},{"name":"Shandong Laboratory of Yantai Drug Discovery and Advanced Research Institute for Drug Discovery , Yantai ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhao","family":"Fang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica , Shanghai ,","place":["China"]},{"name":"University of Chinese Academy of Sciences , Beijing ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Nanjing University of Chinese Medicine , Nanjing ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zihan","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica , Shanghai ,","place":["China"]},{"name":"University of Chinese Academy of Sciences , Beijing ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liqin","family":"Zhou","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica , Shanghai ,","place":["China"]},{"name":"University of Chinese Academy of Sciences , Beijing ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianwei","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Huashan Hospital, Fudan University , Shanghai ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongli","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Huashan Hospital, Fudan University , Shanghai ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongfei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Zhujiang Hospital of Southern Medical University , Guangzhou ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica , Shanghai ,","place":["China"]},{"name":"University of Chinese Academy of Sciences , Beijing ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenyong","family":"Wu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica , Shanghai ,","place":["China"]},{"name":"University of Chinese Academy of Sciences , Beijing ,","place":["China"]},{"name":"Shandong Laboratory of Yantai Drug Discovery and Advanced Research Institute for Drug Discovery , Yantai ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heng","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Plastic and Reconstructive Surgery, Shanghai Jiao Tong University School of Medicine , Shanghai ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengxian","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Zhujiang Hospital of Southern Medical University , Guangzhou ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Feng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica , Shanghai ,","place":["China"]},{"name":"University of Chinese Academy of Sciences , Beijing ,","place":["China"]},{"name":"Department of Anesthesiology, Zhujiang Hospital of Southern Medical University , Guangzhou ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,8,11]]},"container-title":["Brain"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/brain\/advance-article-pdf\/doi\/10.1093\/brain\/awag276\/70606975\/awag276.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/brain\/advance-article-pdf\/doi\/10.1093\/brain\/awag276\/70606975\/awag276.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T06:37:08Z","timestamp":1786430228000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/brain\/advance-article\/doi\/10.1093\/brain\/awag276\/8758669"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,11]]},"references-count":0,"URL":"https:\/\/doi.org\/10.1093\/brain\/awag276","relation":{},"ISSN":["0006-8950","1460-2156"],"issn-type":[{"value":"0006-8950","type":"print"},{"value":"1460-2156","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,11]]},"article-number":"awag276"}}