Cardiac-specific activation of signal transducer and activator of transcription 3 promotes vascular formation in the heart
Cardiac-specific activation of signal transducer and activator of transcription 3 promotes vascular formation in the heart
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DOI：
10.1074/jbc.m108246200
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发表时间：
2002-02-22
影响因子：
4.8
通讯作者：
Kishimoto, T
中科院分区：
文献类型：
--
作者：
Osugi, T;Oshima, Y;Kishimoto, T
信号转导子和转录激活子3（STAT 3）在细胞增殖、分化和细胞存活中起作用。以前，我们已经证明，激活STAT 3是必需的糖蛋白130介导的诱导心肌细胞中的VEGF，但功能的重要性，STAT 3作为血管生成介质仍有待确定。为了解决这个问题，我们首先产生了腺病毒载体表达组成型活性STAT 3（caSTAT 3）。腺病毒介导的caSTAT 3基因转染可诱导培养心肌细胞VEGF表达增加。来自caSTAT 3转染的心肌细胞培养物的条件培养基促进内皮小管形成，其被抗VEGF抗体抑制。接下来，我们产生了心脏特异性过表达caSTAT 3的转基因（TG）小鼠，并证明了caSTAT 3 TG小鼠在心脏中显示出VEGF诱导的证据。CaSTAT 3 TG心脏还表现出毛细血管密度增加，伴随着内皮特异性成分VE-钙粘蛋白表达的增加。这些数据表明，与非转基因心脏相比，caSTAT 3 TG心脏表现出富集的血管结构。本研究提供了第一个证据，表明STAT 3的激活控制体内血管生长，并表明STAT 3通过调节应激条件下的血管功能有助于心脏适应。
Signal transducer and activator of transcription 3 (STAT3) functions in cell proliferation, differentiation, and cell survival. Previously, we have demonstrated that the activation of STAT3 is required for glycoprotein 130-mediated induction of VEGF in cardiac myocytes, but the functional importance of STAT3 as an angiogenic mediator remains to be determined. To address this issue, we first generated the adenoviral vector expressing constitutively active STAT3 (caSTAT3). Adenoviral gene transfer of caSTAT3 induced an increase in the expression of VEGF in cultured cardiomyocytes. The conditioned medium from caSTAT3-transfected cardiomyocyte culture promoted endothelial tubule formation, which was inhibited by anti-VEGF antibody. Next, we generated the transgenic (TG) mice with cardiac-specific overexpression of caSTAT3 and demonstrated that caSTAT3 TG mice showed evidence of VEGF induction in the hearts. The caSTAT3 TG hearts also demonstrated increased capillary density accompanied by an increase in the expression of VE-cadherin, an endothelial-specific component. These data indicate that caSTAT3 TG hearts exhibit an enriched vascular structure compared with non-transgenic hearts. The study presented here provides the first evidence that activation of STAT3 controls vessel growth in vivo and suggests that STAT3 contributes to cardiac adaptation by regulating vascular function under the conditions of stress.