From Center for Stroke Research Berlin (C.J.H., U.H., A.R., U.G., G.L-T., U.D., M.E., C.H.) and Department of Neurology (C.J.H., U.H., M.E., C.H.), Charité-Universitätsmedizin Berlin, Germany; Max-Delbrück Center for Molecular Medicine, Berlin, Germany (F.S., S.A.W., H.K.); Institute of Clinical Neurobiology, University Hospital, University of Würzburg, Germany (M.S.); Cluster of Excellence NeuroCure, Charité-Universitätsmedizin Berlin, Germany (H.K., U.D., M.E.); and German Center for Neurodegenerative Diseases (U.D., M.E.) and German Center for Cardiovascular Diseases (U.D., M.E.), Partner Site, Berlin, Germany.
Circulation. 2015 May 19;131(20):1772-82. doi: 10.1161/CIRCULATIONAHA.114.013003. Epub 2015 Mar 20.
Poststroke angiogenesis contributes to long-term recovery after stroke. Signal transducer and activator of transcription-3 (Stat3) is a key regulator for various inflammatory signals and angiogenesis. It was the aim of this study to determine its function in poststroke outcome.
We generated a tamoxifen-inducible and endothelial-specific Stat3 knockout mouse model by crossbreeding Stat3(floxed/KO) and Tie2-Cre(ERT2) mice. Cerebral ischemia was induced by 30 minutes of middle cerebral artery occlusion. We demonstrated that endothelial Stat3 ablation did not alter lesion size 2 days after ischemia but did worsen functional outcome at 14 days and increase lesion size at 28 days. At this late time point vascular Stat3 expression and phosphorylation were still increased in wild-type mice. Gene array analysis of a CD31-enriched cell population of the neurovascular niche showed that endothelial Stat3 ablation led to a shift toward an antiangiogenic and axon growth-inhibiting micromilieu after stroke, with an increased expression of Adamts9. Remodeling and glycosylation of the extracellular matrix and microglia proliferation were increased, whereas angiogenesis was reduced.
Endothelial Stat3 regulates angiogenesis, axon growth, and extracellular matrix remodeling and is essential for long-term recovery after stroke. It might serve as a potent target for stroke treatment after the acute phase by fostering angiogenesis and neuroregeneration.
脑卒中后血管生成有助于脑卒中后的长期恢复。信号转导子和转录激活子 3（Stat3）是各种炎症信号和血管生成的关键调节剂。本研究旨在确定其在脑卒中后结局中的作用。
我们通过将 Stat3（floxed/KO）和 Tie2-Cre（ERT2）小鼠杂交，生成了一种可诱导的、内皮细胞特异性的 Stat3 敲除小鼠模型。通过 30 分钟大脑中动脉闭塞诱导脑缺血。我们证明，内皮细胞 Stat3 缺失不会改变缺血后 2 天的病变大小，但会导致 14 天时的功能结局恶化，并增加 28 天时的病变大小。在这个晚期时间点，野生型小鼠中的血管 Stat3 表达和磷酸化仍然增加。对神经血管龛中 CD31 富集细胞群的基因阵列分析表明，内皮细胞 Stat3 缺失导致脑卒中后向抗血管生成和抑制轴突生长的微环境转变，Adamts9 表达增加。细胞外基质的重塑和糖基化以及小胶质细胞增殖增加，而血管生成减少。
内皮细胞 Stat3 调节血管生成、轴突生长和细胞外基质重塑，是脑卒中后长期恢复所必需的。它可以作为脑卒中后急性阶段治疗的一个潜在靶点，通过促进血管生成和神经再生来发挥作用。
