Excess centrosomes disrupt vascular lumenization and endothelial cell adherens junctions
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Excess centrosomes disrupt vascular lumenization and endothelial cell adherens junctions Danielle B. Buglak1 · Erich J. Kushner2,4 · Allison P. Marvin2 · Katy L. Davis2 · Victoria L. Bautch1,2,3 Received: 27 November 2019 / Accepted: 8 July 2020 © The Author(s) 2020
Abstract Proper blood vessel formation requires coordinated changes in endothelial cell polarity and rearrangement of cell–cell junctions to form a functional lumen. One important regulator of cell polarity is the centrosome, which acts as a microtubule organizing center. Excess centrosomes perturb aspects of endothelial cell polarity linked to migration, but whether centrosome number influences apical–basal polarity and cell–cell junctions is unknown. Here, we show that excess centrosomes alter the apical–basal polarity of endothelial cells in angiogenic sprouts and disrupt endothelial cell–cell adherens junctions. Endothelial cells with excess centrosomes had narrower lumens in a 3D sprouting angiogenesis model, and zebrafish intersegmental vessels had reduced perfusion following centrosome overduplication. These results indicate that endothelial cell centrosome number regulates proper lumenization downstream of effects on apical–basal polarity and cell–cell junctions. Endothelial cells with excess centrosomes are prevalent in tumor vessels, suggesting how centrosomes may contribute to tumor vessel dysfunction. Keywords Endothelial cell · Centrosome · Junctions · Polarity · Lumen · Angiogenesis
Introduction Angiogenesis is the sprouting of new blood vessels from pre-existing vessels and is crucial during development, pregnancy, wound healing, and tumorigenesis [1–3]. Endothelial cells (EC) form new sprouts to provide conduits for blood flow and create a functional vascular network. This process requires dynamic rearrangement of endothelial cell–cell junctions and establishment of apical–basal polarity [4–8]. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10456-020-09737-7) contains supplementary material, which is available to authorized users. * Victoria L. Bautch [email protected] 1
Curriculum in Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
2
Department of Biology, The University of North Carolina at Chapel Hill, CB#3280, Chapel Hill, NC 27599, USA
3
McAllister Heart Institute, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
4
Department of Biological Sciences, University of Denver, Denver, CO, USA
Lumenization closely follows sprout formation and extension temporally, and many sprout tips have multiple EC that are polarized in the apical–basal axis [9]. However, it is not known how centrosome number contributes to this process. As tumors grow, hypoxia leads to elevated levels of proangiogenic factors that promote neo-angiogenesis to vascularize the tumor. However, the blood vessels surrounding these tumors are often leaky, tortuous, and not properly lumenized [10–12], s
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