Arpin deficiency increases actomyosin contractility and vascular permeability

Abstract

ABSTRACTArpin was discovered as an inhibitor of the Arp2/3 complex localized at the lamellipodial tip of fibroblasts, where it regulated migration steering. Recently, we showed that arpin stabilizes the epithelial barrier in an Arp2/3-dependent manner. However, expression and functions of arpin in endothelial cells (EC) have not yet been described. Arpin mRNA and protein are expressed in EC and downregulated by pro-inflammatory cytokines. Arpin depletion in HUVEC causes the formation of actomyosin stress fibers leading to increased permeability in an Arp2/3-independent manner. Instead, inhibitors of ROCK1 and ZIPK, kinases involved in the generation of stress fibers, normalize the loss-of-arpin effects on actin filaments and permeability. Arpin-deficient mice are viable but show a characteristic vascular phenotype in the lung including edema, microhemorrhage and vascular congestion, increased F-actin levels and vascular permeability. Our data show that, apart from being an Arp2/3 inhibitor, arpin is also a regulator of actomyosin contractility and endothelial barrier integrity.SUMMARYThe expression and functions of arpin in endothelial cells are unknown. We show that arpin controls actomyosin contractility and endothelial barrier integrity in an Arp2/3-independent manner via ROCK1/ZIPK. Arpin-deficient mice are viable, but also show increased basal and induced vascular permeability.Graphical abstract.Current working model for arpin functions in ECs.Under basal conditions arpin is located throughout the cell and enriched at cellular junctions. During inflammation, arpin is downregulated causing the formation of actomyosin actin stress fibers, junction disruption, and increased permeability. Question mark indicates the hitherto unknown mechanism of how arpin controls the activity of ROCK and ZIPK to induce the formation of contractile actin stress fibers.