Nuclear SUN1 stabilizes endothelial cell junctions via microtubules to regulate blood vessel formation
Open Access
- 29 March 2023
- journal article
- research article
- Published by eLife Sciences Publications, Ltd in eLife
Abstract
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 linker of the nucleoskeleton and cytoskeleton (LINC) complex protein SUN1 regulates vascular sprouting and endothelial cell-cell junction morphology and function. Loss of murine endothelial Sun1 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.Funding Information
- National Institutes of Health (R35 HL139950)
- National Institutes of Health (5T32HL069768-17)
- American Heart Association (19PRE34380887)
This publication has 116 references indexed in Scilit:
- Measurement of local permeability at subcellular level in cell models of agonist- and ventilator-induced lung injuryLaboratory Investigation, 2012
- Fiji: an open-source platform for biological-image analysisNature Methods, 2012
- Accumulation of the Inner Nuclear Envelope Protein Sun1 Is Pathogenic in Progeric and Dystrophic LaminopathiesCell, 2012
- Angiogenic Sprouting Requires the Fine Tuning of Endothelial Cell Cohesion by the Raf-1/Rok-α ComplexDevelopmental Cell, 2012
- A conditional knockout resource for the genome-wide study of mouse gene functionNature, 2011
- Actomyosin Tension Exerted on the Nucleus through Nesprin-1 Connections Influences Endothelial Cell Adhesion, Migration, and Cyclic Strain-Induced ReorientationBiophysical Journal, 2010
- UNC-83 coordinates kinesin-1 and dynein activities at the nuclear envelope during nuclear migrationDevelopmental Biology, 2010
- SUN1/2 and Syne/Nesprin-1/2 Complexes Connect Centrosome to the Nucleus during Neurogenesis and Neuronal Migration in MiceNeuron, 2009
- Structural requirements for the assembly of LINC complexes and their function in cellular mechanical stiffnessExperimental Cell Research, 2008
- Microtubule Plus-End-Tracking Proteins Target Gap Junctions Directly from the Cell Interior to Adherens JunctionsCell, 2007