ZO-1 controls endothelial adherens junctions, cell-cell tension, angiogenesis, and barrier formation.
Bottom Line: ZO-1 depletion led to tight junction disruption, redistribution of active myosin II from junctions to stress fibers, reduced tension on VE-cadherin and loss of junctional mechanotransducers such as vinculin and PAK2, and induced vinculin dissociation from the α-catenin-VE-cadherin complex.Claudin-5 depletion only mimicked ZO-1 effects on barrier formation, whereas the effects on mechanotransducers were rescued by inhibition of ROCK and phenocopied by JAM-A, JACOP, or p114RhoGEF down-regulation.ZO-1 was required for junctional recruitment of JACOP, which, in turn, recruited p114RhoGEF.
Affiliation: Department of Cell Biology, UCL Institute of Ophthalmology, University College London, London EC1V 9EL, England, UK.Show MeSH
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Mentions: Angiogenesis requires complex actin reorganization and migration of EC to generate functional new vessels. Hence, we asked whether ZO-1 regulates the angiogenic potential of EC. We first used a migration assay to determine if ZO-1 affected collective cell migration. Fig. 3 (A and B) shows that cells lacking normal ZO-1 expression migrated less. An in vitro Matrigel tubulogenesis assay further revealed that ZO-1 depletion led to reduced network formation in vitro (Fig. S1, A and B). ZO-1 depletion was also found to reduce endothelial sprouting in a 3D microcarrier (MC)-based fibrin gel angiogenesis assay (Fig. 3, C–E). ZO-1 thus regulates the angiogenic potential of HDMEC primary cultures.
Affiliation: Department of Cell Biology, UCL Institute of Ophthalmology, University College London, London EC1V 9EL, England, UK.