Nuclear SUN1 stabilizes endothelial cell junctions via microtubules to regulate blood vessel formation

Endothelial cells line all blood vessels, where they coordinate blood vessel formation and the blood-tissue barrier via regulation of cell-cell junctions. The nucleus also regulates endothelial cell behaviors, but it is unclear how the nucleus contributes to endothelial cell activities at the cell p...

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Bibliographic Details
Published in:	eLife Vol. 12
Main Authors:	Buglak, Danielle B, Bougaran, Pauline, Kulikauskas, Molly R, Liu, Ziqing, Monaghan-Benson, Elizabeth, Gold, Ariel L, Marvin, Allison P, Burciu, Andrew, Tanke, Natalie T, Oatley, Morgan, Ricketts, Shea N, Kinghorn, Karina, Johnson, Bryan N, Shiau, Celia E, Rogers, Stephen, Guilluy, Christophe, Bautch, Victoria L
Format:	Journal Article
Language:	English
Published:	England eLife Science Publications, Ltd 29-03-2023 eLife Sciences Publications, Ltd eLife Sciences Publications Ltd
Subjects:	adherens junctions Animals blood vessels Cell Biology endothelial cells Endothelial Cells - metabolism Endothelium Intercellular Junctions - metabolism Mice Microtubule-Associated Proteins - metabolism microtubules Microtubules - metabolism Neovascularization nuclear LINC complex Nuclear Proteins - metabolism SUN1 Zebrafish - metabolism Canada Fiji SUN1 endothelial cells angiogenesis contractility endothelial cell nuclear LINC complex blood vessels microtubules adherens junctions mouse cell biology Nesprin-1 Rho GEF-H1 zebrafish
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Summary:	Endothelial cells line all blood vessels, where they coordinate blood vessel formation and the blood-tissue barrier via regulation of cell-cell junctions. The nucleus also regulates endothelial cell behaviors, but it is unclear how the nucleus contributes to endothelial cell activities at the cell periphery. Here, we show that the nuclear-localized nker of the ucleoskeleton and ytoskeleton (LINC) complex protein SUN1 regulates vascular sprouting and endothelial cell-cell junction morphology and function. Loss of murine endothelial impaired blood vessel formation and destabilized junctions, angiogenic sprouts formed but retracted in SUN1-depleted sprouts, and zebrafish vessels lacking Sun1b had aberrant junctions and defective cell-cell connections. At the cellular level, SUN1 stabilized endothelial cell-cell junctions, promoted junction function, and regulated contractility. Mechanistically, SUN1 depletion altered cell behaviors via the cytoskeleton without changing transcriptional profiles. Reduced peripheral microtubule density, fewer junction contacts, and increased catastrophes accompanied SUN1 loss, and microtubule depolymerization phenocopied effects on junctions. Depletion of GEF-H1, a microtubule-regulated Rho activator, or the LINC complex protein nesprin-1 rescued defective junctions of SUN1-depleted endothelial cells. Thus, endothelial SUN1 regulates peripheral cell-cell junctions from the nucleus via LINC complex-based microtubule interactions that affect peripheral microtubule dynamics and Rho-regulated contractility, and this long-range regulation is important for proper blood vessel sprouting and junction integrity.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, United States.
ISSN:	2050-084X 2050-084X
DOI:	10.7554/elife.83652