Vascular endothelial tyrosine phosphatase (VE-PTP)-null mice undergo vasculogenesis but die embryonically because of defects in angiogenesis
Vascular endothelial tyrosine phosphatase (VE-PTP)-null mice undergo vasculogenesis but die embryonically because of defects in angiogenesis
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DOI：
10.1073/pnas.0611510104
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发表时间：
2007-02-27
影响因子：
11.1
通讯作者：
Gale, Nicholas W.
中科院分区：
文献类型：
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作者：
Dominguez, Melissa G.;Hughes, Virginia C.;Gale, Nicholas W.
血管系统的发育依赖于多种血管生成调节因子的高度协调作用。这些调节剂中的几种是酪氨酸激酶超家族的成员，包括VEGF受体和血管生成素受体，蒂尔和Tie 2。酪氨酸激酶信号传导由酪氨酸磷酸酶的活性反调节，包括血管内皮蛋白酪氨酸磷酸酶（VE-PTP），其先前已显示调节Tie 2活性。我们产生了VE-PTP被报告基因取代的小鼠。我们证实VE-PTP在内皮细胞中表达，并且还表明VE-PTP在发育中的心脏流出道中高度表达，随后在发育中的心脏瓣膜中表达。血管生成在缺乏VE-PTP的小鼠中正常发生;然而，血管生成是异常的。VE-PTP-null小鼠中的血管生成缺陷在卵黄囊中最明显，并且包括将原始血管支架精细加工成高阶分支动脉、静脉和毛细血管的完全失败。VE-PTP持续在血管系统和心脏瓣膜中表达至成年期，表明其在血管发育或体内平衡中的后期作用。VE-PTP也在生长肿瘤的血管系统中表达，这表明VE-PTP可能是血管生成治疗的新的潜在靶点。
Development of the vascular system depends on the highly coordinated actions of a variety of angiogenic regulators. Several of these regulators are members of the tyrosine kinase superfamily, including VEGF receptors and angiopoietin receptors, Tiel and Tie2. Tyrosine kinase signaling is counter-regulated by the activity of tyrosine phosphatases, including vascular endothelial protein tyrosine phosphatase (VE-PTP), which has previously been shown to modulate Tie2 activity. We generated mice in which VE-PTP is replaced with a reporter gene. We confirm that VE-PTP is expressed in endothelium and also show that VE-PTP is highly expressed in the developing outflow tract of the heart and later is expressed in developing heart valves. Vasculogenesis occurs normally in mice lacking VE-PTP; however, angiogenesis is abnormal. Angiogenic defects in VE-PTP-null mice were most pronounced in the yolk sac and include a complete failure to elaborate the primitive vascular scaffold into higher-order branched arteries, veins, and capillaries. VE-PTP continues to be expressed into adulthood in the vasculature and heart valves, suggesting later roles in vascular development or homeostasis. VE-PTP is also expressed in the vasculature of growing tumors, suggesting that VE-PTP may be a new potential target for angiogenic therapies.