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Angiogenic factor signaling regulates centrosome duplication in endothelial cells of developing blood vessels.

ABSTRACT: 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.

SUBMITTER: Taylor SM

PROVIDER: S-EPMC2974614 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Angiogenic factor signaling regulates centrosome duplication in endothelial cells of developing blood vessels.

Taylor Sarah M SM Nevis Kathleen R KR Park Hannah L HL Rogers Gregory C GC Rogers Stephen L SL Cook Jeanette G JG Bautch Victoria L VL

Blood 20100727 16

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 endo ...[more]

PMID: 20664058

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Project description:Tumor Endothelial Marker 8/Anthrax Toxin Receptor 1 (TEM8/ANTXR1) expression is induced in the vascular compartment of multiple tumors and therefore, is a candidate molecule to target tumor therapies. This cell surface molecule mediates anthrax toxin internalization, however, its physiological function in blood vessels remains largely unknown. We identified the chicken chorioallantoic membrane (CAM) as a model system to study the endogenous function of TEM8 in blood vessels as we found that TEM8 expression was induced transiently between day 10 and 12 of embryonic development, when the vascular tree is undergoing final development and growth. We used the cell-binding component of anthrax toxin, Protective Antigen (PA), to engage endogenous TEM8 receptors and evaluate the effects of PA-TEM8 complexes on vascular development. PA applied at the time of highest TEM8 expression reduced vascular density and disrupted hierarchical branching as revealed by quantitative morphometric analysis of the vascular tree after 48h. PA-dependent reduced branching phenotype was partially mimicked by Wnt3a application and ameliorated by the Wnt antagonist, Dikkopf-1. These results implicate TEM8 expression in endothelial cells in regulating the canonical Wnt signaling pathway at this day of CAM development. Consistent with this model, PA increased beta catenin levels acutely in CAM blood vessels in vivo and in TEM8 transfected primary human endothelial cells in vitro. TEM8 expression in Hek293 cells, which neither express endogenous PA-binding receptors nor Wnt ligands, stabilized beta catenin levels and amplified beta catenin-dependent transcriptional activity induced by Wnt3a. This agonistic function is supported by findings in the CAM, where the increase in TEM8 expression from day 10 to day 12 and PA application correlated with Axin 2 induction, a universal reporter gene for canonical Wnt signaling. We postulate that the developmentally controlled expression of TEM8 modulates endothelial cell response to canonical Wnt signaling to regulate vessel patterning and density.

Dataset Information

Angiogenic factor signaling regulates centrosome duplication in endothelial cells of developing blood vessels.

Publications

Angiogenic factor signaling regulates centrosome duplication in endothelial cells of developing blood vessels.

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