Heparan sulfate in trans potentiates VEGFR-mediated angiogenesis
Heparan sulfate in trans potentiates VEGFR-mediated angiogenesis
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DOI：
10.1016/j.devcel.2006.03.009
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发表时间：
2006-05-01
影响因子：
11.8
通讯作者：
Claesson-Welsh, Lena
中科院分区：
文献类型：
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作者：
Jakobsson, Lars;Kreuger, Johan;Claesson-Welsh, Lena
一些受体酪氨酸激酶需要硫酸肝素蛋白聚糖（HSPGs）作为有效信号转导的辅助受体。我们研究了HSPGs在胚胎干细胞毛细血管结构发育中的作用，这一过程严格依赖于血管内皮生长因子受体-2 （VEGFR-2）的信号传导。我们通过使用在HS生成或VEGFR-2合成上有缺陷的胚胎干细胞嵌合培养，证明内皮细胞中的VEGF信号完全由邻近血管周围平滑肌细胞反式表达的HS支持。由于活性VEGFR-2信号复合物的hs依赖性捕获，VEGFR-2的转激活导致信号转导延长和增强。我们的数据表明，通过HSPG核心蛋白的直接信号传导对于内皮细胞的功能性VEGF反应是必不可少的。我们认为HSPGs对酪氨酸激酶受体的反激活构成了相邻细胞间串扰的机制。
Several receptor tyrosine kinases require heparan sulfate proteoglycans (HSPGs) as coreceptors for efficient signal transduction. We have studied the role of HSPGs in the development of blood capillary structures from embryonic stem cells, a process strictly dependent on signaling via vascular endothelial growth factor receptor-2 (VEGFR-2). We show, by using chimeric cultures of embryonic stem cells defective in either HS production or VEGFR-2 synthesis, that VEGF signaling in endothelial cells is fully supported by HS expressed in trans by adjacent perivascular smooth muscle cells. Transactivation of VEGFR-2 leads to prolonged and enhanced signal transduction due to HS-dependent trapping of the active VEGFR-2 signaling complex. Our data imply that direct signaling via HSPG core proteins is dispensable for a functional VEGF response in endothelial cells. We propose that transactivation of tyrosine kinase receptors by HSPGs constitutes a mechanism for crosstalk between adjacent cells.