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

• 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
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/elife.83652

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.