Stretch induces upregulation of key tyrosine kinase receptors in microvascular endothelial cells.
Stretch induces upregulation of key tyrosine kinase receptors in microvascular endothelial cells.
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DOI：
10.1152/ajpheart.00410.2004
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发表时间：
2004-12
期刊：
影响因子：
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通讯作者：
Wei Zheng;Lance P. Christensen;R. Tomanek
中科院分区：
文献类型：
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作者：
Wei Zheng;Lance P. Christensen;R. Tomanek
我们先前证明，心肌细胞的周期性伸展通过血管内皮生长因子（VEGF）激活旁分泌信号，导致血管生成。本研究验证了周期性牵张上调大鼠冠状动脉微血管内皮细胞（RCMEC）和人脐静脉内皮细胞（HUVEC）酪氨酸激酶受体的假设。VEGF受体-2（Flk-1）蛋白水平在HUVEC和RCMEC中以时间依赖性方式增加，但RCMEC中的增加比HUVEC早得多。Flk-1蛋白水平的增强不受VEGF中和抗体的抑制，表明VEGF不参与牵张诱导的Flk-1表达。VEGF受体-1（Flt-1）蛋白和mRNA不受牵张的影响。然而，Tie-2和Tie-1蛋白水平在RCMEC中增加。血管生成素-1和-2，Tie-2的配体，增加心肌细胞进行周期性拉伸，但不受拉伸内皮细胞（EC）。拉伸或孵育RCMEC与VEGF适度增加细胞增殖，而拉伸+ VEGF对增殖有累加效应。机械牵张诱导血管EC中关键酪氨酸激酶受体Flk-1、Tie-2和Tie-1的上调，这是EC对生长因子的敏感性增加的基础，因此促进血管生成。这些体外研究结果支持了心肌细胞和EC伸展在冠状动脉血管生成中起关键作用的概念。
We previously demonstrated that cyclic stretch of cardiac myocytes activates paracrine signaling via vascular endothelial growth factor (VEGF) leading to angiogenesis. The present study tested the hypothesis that cyclic stretch upregulates tyrosine kinase receptors in rat coronary microvascular endothelial cells (RCMEC) and human umbilical vein endothelial cells (HUVEC). VEGF receptor-2 (Flk-1) protein levels increased in HUVEC and RCMEC in a time-dependent manner, but the increase occurred much earlier in RCMEC than in HUVEC. The enhancement of Flk-1 protein level was not inhibited by addition of VEGF neutralizing antibodies, indicating that VEGF is not involved in stretch-induced Flk-1 expression. VEGF receptor-1 (Flt-1) protein and mRNA were not changed by stretch. However, Tie-2 and Tie-1 protein levels increased in RCMEC. Angiopoietin-1 and -2, the ligands for Tie-2, increased in cardiac myocytes subjected to cyclic stretch but were not affected by stretch in endothelial cells (EC). Stretch or incubation of RCMEC with VEGF increased cell proliferation moderately, whereas stretch + VEGF had an additive effect on proliferation. Mechanical stretch induces upregulation of the key tyrosine kinase receptors Flk-1, Tie-2, and Tie-1 in vascular EC, which underlies the increase in sensitivity of EC to growth factors and, therefore, facilitates angiogenesis. These in vitro findings support the concept that stretch of cardiac myocytes and EC plays a key role in coronary angiogenesis.