Angiogenic factor signaling regulates centrosome duplication in endothelial cells of developing blood vessels.
Regulated vascular endothelial growth factor (VEGF) signaling is required for proper angiogenesis, and excess VEGF signaling results in aberrantly formed vessels that do not function properly. Tumor endothelial cells have excess centrosomes and are aneuploid, properties that probably contribute to the morphologic and functional abnormalities of tumor vessels. We hypothesized that endothelial cell centrosome number is regulated by signaling via angiogenic factors, such as VEGF. We found that endothelial cells in developing vessels exposed to elevated VEGF signaling display centrosome overduplication. Signaling from VEGF, through either MEK/ERK or AKT to cyclin E/Cdk2, is amplified in association with centrosome overduplication, and blockade of relevant pathway components rescued the centrosome overduplication defect. Endothelial cells exposed to elevated FGF also had excess centrosomes, suggesting that multiple angiogenic factors regulate centrosome number. Endothelial cells with excess centrosomes survived and formed aberrant spindles at mitosis. Developing vessels exposed to elevated VEGF signaling also exhibited increased aneuploidy of endothelial cells, which is associated with cellular dysfunction. These results provide the first link between VEGF signaling and regulation of the centrosome duplication cycle, and suggest that endothelial cell centrosome overduplication contributes to aberrant angiogenesis in developing vessel networks exposed to excess angiogenic factors.
Taylor
Sarah M
SM
Department of Biology, University of North Carolina, Chapel Hill, NC 27599, USA.
Nevis
Kathleen R
KR
Park
Hannah L
HL
Rogers
Gregory C
GC
Rogers
Stephen L
SL
Cook
Jeanette G
JG
Bautch
Victoria L
VL
D000782:Aneuploidy; D043925:Angiogenesis Inducing Agents / Q000378:metabolism*; D000818:Animals; D001808:Blood Vessels / Q000254:growth & development* / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D002478:Cells, Cultured; D018385:Centrosome / Q000378:metabolism*; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D015017:Yolk Sac / Q000166:cytology
D043925:Angiogenesis Inducing Agents; D019927:Cyclin E; D042461:Vascular Endothelial Growth Factor A; D051057:Proto-Oncogene Proteins c-akt; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D020929:Mitogen-Activated Protein Kinase Kinases