VEGF regulates centrosome duplication and division orientation in endothelial cells of developing blood vessels Public Deposited

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Last Modified
  • March 22, 2019
Creator
  • Taylor, Sarah Maria
    • Affiliation: College of Arts and Sciences, Department of Biology
Abstract
  • Blood vessel formation is critical for vertebrate development and is required for the progression of many diseases, including cancer. Thus, understanding how blood vessels form and function is a necessary prerequisite to treating and preventing human disease. Vascular Endothelial Growth Factor-A (VEGF) activates signaling cascades in endothelial cells to promote survival, migration and proliferation; and elevated VEGF signaling yields overgrown, dysfunctional vessels. Tumor vessels experience high VEGF signaling and are abnormal in many ways. Of interest, tumor vessels have excess centrosomes and display aneuploidy; and they are tortuous and over-grown. I hypothesized that these abnormalities result from elevated VEGF signaling. I used developmental models of elevated VEGF signaling to test my hypothesis. I showed that VEGF gain-of-function flt-1-/- embryonic stem (ES) cell-derived vessels and in vivo yolk sac vessels display centrosome over-duplication and aneuploidy. Moreover, VEGF signals through MEK/ERK and AKT to cyclin E/Cdk2 to promote centrosome over-duplication. Interestingly, cells with excess centrosomes are enriched at the leading edge of in vitro scratch wounds, indicating that endothelial cells with excess centrosomes have a migratory advantage. I also wondered if elevated VEGF signaling affects endothelial cell division orientation to disrupt proper vascular morphogenesis. In collaboration with Dr. Gefei Zeng, I showed that endothelial cell divisions are normally oriented to increase the long axis of developing vessels in ES cell-derived vessels and in vivo in neonatal retinal vessels. Furthermore, flt-1-/- endothelial cell divisions are randomly oriented compared to wildtype divisions. Randomized division orientations lead to dysmorphogenesis in other tissue types and it is possible that randomized endothelial cell divisions contribute to vascular dysmorphogenesis. My data describe new roles for VEGF signaling during developmental blood vessel formation and suggest novel mechanisms as to how pathological vessels, such as tumor vessels, become abnormal.
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  • In Copyright
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  • "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Biology."
Advisor
  • Bautch, Victoria
Degree granting institution
  • University of North Carolina at Chapel Hill
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  • Chapel Hill, NC
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  • Open access
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