Universität Heidelberg, Medizinische Fakultät Mannheim, Mannheim, Germany.
Blood. 2012 Aug 30;120(9):1899-907. doi: 10.1182/blood-2011-09-376657. Epub 2012 Jul 13.
VEGFR-3 is a transmembrane receptor tyrosine kinase that is activated by its ligands VEGF-C and VEGF-D. Although VEGFR-3 has been linked primarily to the regulation of lymphangiogenesis, in the present study, we demonstrate a role for VEGFR-3 in megakaryopoiesis. Using a human erythroleukemia cell line and primary murine BM cells, we show that VEGFR-3 is expressed on megakaryocytic progenitor cells through to the promegakaryoblast stage. Functionally, specific activation of VEGFR-3 impaired the transition to polyploidy of CD41+ cells in primary BM cultures. Blockade of VEGFR-3 promoted endoreplication consistently. In vivo, long-term activation or blockade of VEGFR-3 did not affect steady-state murine megakaryopoiesis or platelet counts significantly. However, activation of VEGFR-3 in sublethally irradiated mice resulted in significantly elevated numbers of CD41+ cells in the BM and a significant increase in diploid CD41+ cells, whereas the number of polyploid CD41+ cells was reduced significantly. Moreover, activation of VEGFR-3 increased platelet counts in thrombopoietin-treated mice significantly and modulated 5-fluorouracil-induced thrombocytosis strongly, suggesting a regulatory role for VEGFR-3 in megakaryopoiesis.
VEGFR-3 是一种跨膜受体酪氨酸激酶，其配体 VEGF-C 和 VEGF-D 可激活它。尽管 VEGFR-3 主要与淋巴管生成的调节有关，但在本研究中，我们证明了它在巨核细胞生成中的作用。我们使用人红白血病细胞系和原代鼠 BM 细胞表明，VEGFR-3 表达于巨核细胞祖细胞，直至前巨核细胞阶段。功能上，VEGFR-3 的特异性激活会损害原代 BM 培养物中 CD41+细胞向多倍体的转变。VEGFR-3 的阻断会一致促进内复制。在体内，VEGFR-3 的长期激活或阻断对稳态小鼠巨核细胞生成或血小板计数没有明显影响。然而，在亚致死照射的小鼠中激活 VEGFR-3 会导致 BM 中 CD41+细胞数量显著增加，并使二倍体 CD41+细胞显著增加，而多倍体 CD41+细胞的数量则显著减少。此外，VEGFR-3 的激活会显著增加血小板生成素处理小鼠的血小板计数，并强烈调节 5-氟尿嘧啶诱导的血小板增多症，这表明 VEGFR-3 在巨核细胞生成中起调节作用。
