Roles of vascular endothelial growth factor receptor 3 signaling in differentiation of mouse embryonic stem cell-derived vascular progenitor cells into endothelial cells
Roles of vascular endothelial growth factor receptor 3 signaling in differentiation of mouse embryonic stem cell-derived vascular progenitor cells into endothelial cells
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DOI：
10.1182/blood-2004-07-2547
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发表时间：
2005-03-15
期刊：
影响因子：
20.3
通讯作者：
Miyazono, K
中科院分区：
文献类型：
--
作者：
Suzuki, H;Watabe, T;Miyazono, K
胚胎干细胞来源的血管内皮细胞生长因子受体2(VEGFR2/Flk-1)阳性细胞可作为血管前体细胞，在血管内皮生长因子-A(VEGF-A)存在下分化为内皮细胞(ECs)。VEGFR3/Flt-4(FMS样酪氨酸激酶4)信号通路在淋巴管内皮细胞(LECs)的发育中起重要作用。为了阐明VEGFR3信号在血管前体细胞向内皮细胞分化中的作用，我们将不同类型的VEGFR3 cDNAs导入小鼠ES细胞。VEGFR2和VEGFR3的配体VEGF-C可促进VEGFR2(+)细胞向内皮细胞分化，但不能促进VEGFR2(+)细胞的内皮分化。血管内皮细胞生长因子受体-1(LYVE-1)高表达淋巴管内皮细胞透明质酸受体-1，并与透明质酸有效结合。能够激活VEGFR3但不能激活VEGFR2的VEGF-C(C152S)不能诱导VEGFR2(+)细胞向内皮细胞分化，提示VEGFR2信号在血管内皮细胞分化中起重要作用。此外，VEGFR3的激酶阴性突变体阻止了血管内皮生长因子-C介导的血管前体细胞的内皮分化。因此，在血管内皮生长因子-C诱导的小鼠ES细胞的内皮分化过程中，VEGFR2信号是必需的，而VEGFR3信号可能赋予内皮细胞淋巴管内皮样表型。(C)2005年，由美国血液病学会提供。
Vascular endothelial growth factor receptor 2 (VEGFR2/Flk-1)-positive cells derived from embryonic stem (ES) cells serve as vascular progenitors, which differentiate into endothelial cells (ECs) in the presence of VEGF-A. VEGFR3/Flt-4 (fms-like tyrosine kinase 4) signaling is known to be important for the development of lymphatic endothelial cells (LECs). To elucidate the roles of VEGFR3 signaling in the differentiation of vascular progenitor cells into ECs, we introduced various types of VEGFR3 cDNAs into mouse ES cells. VEGF-C, a ligand for VEGFR2 and VEGFR3, stimulated the endothelial differentiation of the VEGFR2(+) cells transfected with the VEGFR3 cDNA but not those transfected with kinase-negative mutants of VEGFR3. The VEGFR3-transfected ECs exhibited high expression levels of lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1), one of the markers of LECs, and showed efficient binding of hyaluronan. VEGF-C(C152S), which is able to activate VEGFR3 but not VEGFR2, failed to induce the endothelial differentiation of mock- and VEGFR3-transfected VEGFR2(+) cells, suggesting the essential role of VEGFR2 signaling for endothelial differentiation. Furthermore, kinase-negative mutants of VEGFR3 prevented the VEGF-C-mediated endothelial differentiation of the vascular progenitor cells. Thus, VEGFR2 signaling is required for the endothelial differentiation of mouse ES cells induced by VEGF-C, and VEGFR3 signaling may confer lymphatic endothelial-like phenotypes to ECs. (c) 2005 by The American Society of Hematology.