Elevated VEGF Signaling Leads to Centrosome Over-duplication and Multinucleate Cell Accumulation in Endothelial Cells (2010)

Undergraduates: Hannah Park, Sarah M. Taylor

Faculty Advisor: Victoria Bautch
Department: Biology

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Blood vessel formation is a critical process during both normal and pathological development because blood vessels mediate the delivery of oxygen and nutrients to tissues. Vascular Endothelial Growth Factor-A (VEGF) promotes blood vessel formation, and elevated VEGF signaling, like that found in tumors, leads to aberrant vessel formation. In tumors, elevated VEGF signaling leads to blood vessel over-growth and leakiness. At the cellular level, the endothelial cells that make up tumor vessels contain excess centrosomes and display aneuploidy, and we investigated whether these defects are caused by elevated VEGF signaling. We treated Human Umbilical Vein Endothelial Cells (HUVEC) with low or high levels of VEGF and found that high VEGF signaling promotes centrosome over-duplication in endothelial cells via MAPK and AKT signaling to cyclin E/Cdk2. We also found that elevated VEGF signaling leads to multinucleate endothelial cells, which may result from incomplete cytokinesis. Furthermore, we show that tumor-derived endothelial cells display increased frequencies of excess centrosomes and multinucleate cells in vivo compared to the same cells cultured in vitro, suggesting that the in vivo environment is more conducive to the accumulation of endothelial cell abnormalities. Understanding how elevated VEGF signaling impacts endothelial cells is critical for the development of therapies aimed at inhibiting tumor blood vessel growth.