VEGFR-3 is expressed on megakaryocyte precursors in the murine bone marrow and plays a regulatory role in megakaryopoiesis.
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.
Universität Heidelberg, Medizinische Fakultät Mannheim, Mannheim, Germany. wilko.thiele@medma.uni-heidelberg.de
Wilko
W
Thiele
Jaya
J
Krishnan
Melanie
M
Rothley
Debra
D
Weih
Diana
D
Plaumann
Vanessa
V
Kuch
Luca
L
Quagliata
Herbert A
HA
Weich
Jonathan P
JP
Sleeman
D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005472:Fluorouracil / Q000494:pharmacology; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D055016:Megakaryocyte Progenitor Cells / Q000187:drug effects / Q000378:metabolism*; D008533:Megakaryocytes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010703:Phorbol Esters / Q000494:pharmacology; D010976:Platelet Count; D040201:Platelet Membrane Glycoprotein IIb / Q000378:metabolism; D011003:Ploidies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D034061:Thrombopoiesis; D013926:Thrombopoietin / Q000494:pharmacology; D042582:Vascular Endothelial Growth Factor C / Q000494:pharmacology; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics / Q000378:metabolism*
D000963:Antimetabolites; D010703:Phorbol Esters; D040201:Platelet Membrane Glycoprotein IIb; D042582:Vascular Endothelial Growth Factor C; D013926:Thrombopoietin; D040321:Vascular Endothelial Growth Factor Receptor-3; D005472:Fluorouracil