Transcriptional profiling reveals a critical role for tyrosine phosphatase VE-PTP in regulation of VEGFR2 activity and endothelial cell morphogenesis
Transcriptional profiling reveals a critical role for tyrosine phosphatase VE-PTP in regulation of VEGFR2 activity and endothelial cell morphogenesis
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DOI：
10.1096/fj.08-123810
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发表时间：
2009-05-01
期刊：
影响因子：
4.8
通讯作者：
Claesson-Welsh, Lena
中科院分区：
文献类型：
--
作者：
Mellberg, Sofie;Dimberg, Anna;Claesson-Welsh, Lena
为了确定伴随三维(3D)血管管形成的分子事件，我们研究了血管内皮生长因子(VEGF)诱导内皮细胞管状形态发生过程中的基因表达。微阵列分析比较了从3D胶原培养中获得的生长停滞、管状内皮细胞和纤维连接蛋白上培养的增殖内皮细胞中的基因诱导。通过公开可用的数据集，对差异表达的基因进行聚类并分析特定的内皮表达。我们验证了其中一个已识别的基因，血管内皮细胞蛋白酪氨酸磷酸酶(VE-PTP)对内皮细胞形态发生的贡献。VE-PTP表达的沉默伴随着血管内皮生长因子受体-2(VEGFR2)酪氨酸磷酸化和下游信号通路的激活。在3D培养中，VEGFR2活性的增加促进了内皮细胞周期的进展，克服了与组织成管状结构相关的G(0)/G(1)停滞。在静息细胞中，近距离结扎显示VEGFR2与VE-PTP密切相关。血管内皮细胞生长因子受体2被血管内皮生长因子激活后迅速失去结合，并随着受体活性的降低而逐渐恢复。总而言之，我们已经确定了在血管形成中可能起关键作用的基因。其中一种是VE-PTP，它调节VEGFR2的活性，从而在血管生成过程中调节VEGFR2的反应。-Mellberg，S.，Dimberg，A.，Babram，F.，Hayashi，M.，Rennel，E.，Ameur，A.，Westholm，J.O.，Larsson，E.，Lindahl，P.，Cross，M.J.，Claesson-Welsh，L.转录图谱显示，酪氨酸磷酸酶VE-PTP在调节VEGFR2的活性和内皮细胞形态发生中发挥关键作用。FASE B J.23,1490-1502(2009)
To define molecular events accompanying formation of the 3-dimensional (3D) vascular tube, we have characterized gene expression during vascular endothelial growth factor (VEGF)-induced tubular morphogenesis of endothelial cells. Microarray analyses were performed comparing gene induction in growth-arrested, tube-forming endothelial cells harvested from 3D collagen cultures to that in proliferating endothelial cells cultured on fibronectin. Differentially expressed genes were clustered and analyzed for specific endothelial expression through publicly available datasets. We validated the contribution of one of the identified genes, vascular endothelial protein tyrosine phosphatase (VE-PTP), to endothelial morphogenesis. Silencing of VE-PTP expression was accompanied by increased VEGF receptor-2 (VEGFR2) tyrosine phosphorylation and activation of downstream signaling pathways. The increased VEGFR2 activity promoted endothelial cell cycle progression, overcoming the G(0)/G(1) arrest associated with organization into tubular structures in the 3D cultures. Proximity ligation showed close association between VEGFR2 and VE-PTP in resting cells. Activation of VEGFR2 by VEGF led to rapid loss of association, which was resumed with time in parallel with decreased receptor activity. In conclusion, we have identified genes, which may serve critical functions in formation of the vascular tube. One of these, VE-PTP, regulates VEGFR2 activity thereby modulating the VEGF-response during angiogenesis.-Mellberg, S., Dimberg, A., Bahram, F., Hayashi, M., Rennel, E., Ameur, A., Westholm, J. O., Larsson, E., Lindahl, P., Cross, M. J., Claesson-Welsh, L. Transcriptional profiling reveals a critical role for tyrosine phosphatase VE-PTP in regulation of VEGFR2 activity and endothelial cell morphogenesis. FASEB J. 23, 1490-1502 (2009)