Centrosomes nucleate microtubules in cells, and organize them via a microtubule organizing center (MTOC) during interphase and via spindles during mitosis. Centrosome duplication is normally tightly regulated to occur once and only once per cell cycle, and loss of this regulation leads to excess centrosomes, genetic instability, and aneuploidy in tumor cells. We recently showed, for the first time, that endothelial cells (EC) in blood vessels exposed to elevated VEGF-A signaling have excess centrosomes, mediated through Akt, MEK/ERK, and Cdk2/cyclin E. Centrosome excess is predicted to perturb the cytoskeleton and result in alterations in cellular behaviors, although this link has not been made in cells or tissues;it also is predicted to produce chromosome instability and aneuploidy, leading to EC with profound changes from the norm. This work will test the hypothesis that excess centrosomes in EC perturb vessel function via both mitotic and non-mitotic perturbations, and examine the mechanisms that lead to centrosome mis-regulation upon angiogenic factor stimulation. This highly innovative hypothesis will be tested with three aims that address the questions: 1) What are the inputs and mechanisms that lead to EC centrosome mis- regulation? 2) What are the consequences of excess centrosomes to EC behaviors and sprouting? and 3) what are the outcomes of excess centrosomes in EC of vessels in vivo? We will utilize cell- based models of blood vessel formation and in vivo mouse developmental and disease models to address the questions. The significance of this work will be to reveal susceptibility in developing vessels for centrosome-mediated EC dysfunction and genetic instability, which is predicted to contribute to blood vessel dysfunction in novel ways, and lead to new and distinct therapeutic targets.

Public Health Relevance

Cell division normally segregates genetic material, or chromosomes, equally to two daughter cells. It has long been known that tumor cells have defects that often lead to unequal segregation of chromosomes, resulting in further mutation of tumor cells to malignancy. We recently discovered that non-tumor endothelial cells can also acquire the defects leading to mis-segregation of chromosomes, and we aim to better understand how this occurs, and the consequences of these defects on blood vessel formation, which can lead to new therapies.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiovascular Differentiation and Development Study Section (CDD)
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Gao, Yunling
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University of North Carolina Chapel Hill
Schools of Arts and Sciences
Chapel Hill
United States
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Arreola, Alexandra; Payne, Laura Beth; Julian, Morgan H et al. (2018) Von Hippel-Lindau mutations disrupt vascular patterning and maturation via Notch. JCI Insight 3:
Nesmith, Jessica E; Chappell, John C; Cluceru, Julia G et al. (2017) Blood vessel anastomosis is spatially regulated by Flt1 during angiogenesis. Development 144:889-896
Chong, Diana C; Yu, Zhixian; Brighton, Hailey E et al. (2017) Tortuous Microvessels Contribute to Wound Healing via Sprouting Angiogenesis. Arterioscler Thromb Vasc Biol 37:1903-1912
Lee, Heon-Woo; Chong, Diana C; Ola, Roxana et al. (2017) Alk2/ACVR1 and Alk3/BMPR1A Provide Essential Function for Bone Morphogenetic Protein-Induced Retinal Angiogenesis. Arterioscler Thromb Vasc Biol 37:657-663
Yu, Zhixian; Ruter, Dana L; Kushner, Erich J et al. (2017) Excess centrosomes induce p53-dependent senescence without DNA damage in endothelial cells. FASEB J 31:4295-4304
Bautch, Victoria L (2017) Endoglin moves and shapes endothelial cells. Nat Cell Biol 19:593-595
Kushner, Erich J; Ferro, Luke S; Yu, Zhixian et al. (2016) Excess centrosomes perturb dynamic endothelial cell repolarization during blood vessel formation. Mol Biol Cell 27:1911-20
Mouillesseaux, Kevin P; Wiley, David S; Saunders, Lauren M et al. (2016) Notch regulates BMP responsiveness and lateral branching in vessel networks via SMAD6. Nat Commun 7:13247
Bautch, Victoria L; Caron, Kathleen M (2015) Blood and lymphatic vessel formation. Cold Spring Harb Perspect Biol 7:a008268
Dudley, Andrew C; Bautch, Victoria L (2015) Feeding cancer's sweet tooth: specialized tumour vasculature shuttles glucose in pancreatic ductal adenocarcinoma. J Pathol 236:133-5

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