Abstract
ABSTRACTMutations in the cytoskeletal linker protein plectin result in multisystemic diseases affecting skin and muscle with indications of additional vascular system involvement. To study the mechanisms underlying vascular disorders, we established plectin-deficient endothelial cell and mouse models. We show that apart from perturbing the vimentin cytoskeleton of endothelial cells, plectin deficiency leads to severe distortions of adherens junctions (AJs), as well as tight junctions, accompanied by an upregulation of actin stress fibres and increased cellular contractility. Plectin-deficient endothelial cell layers were more leaky and showed reduced mechanical resilience in fluid-shear stress and mechanical stretch experiments. We suggest that the distorted AJs and upregulated actin stress fibres in plectin-deficient cells are rooted in perturbations of the vimentin cytoskeleton, as similar phenotypes could be mimicked in wild-type cells by disruption of vimentin filaments. In vivo studies in endothelium-restricted conditional plectin-knockout mice revealed significant distortions of AJs in stress-prone aortic arch regions and increased pulmonary vascular leakage. Our study opens a new perspective on cytoskeleton-controlled vascular permeability, where a plectin-organized vimentin scaffold keeps actomyosin contractility ‘in-check’ and maintains AJ homeostasis.
Highlights
Weakened endothelial junctions lead to increased permeability and compromised vascular integrity causing haemorrhage, brain and pulmonary oedema, acute respiratory distress syndrome and increased susceptibility to stress induced injury (Maniatis and Orfanos, 2008)
Plectin-null mice show vascular defects To assess whether vascular defects contribute to haemorrhagic blister formation in plectin-deficient mice, we comparatively analysed the blistering phenotype of mice that were lacking plectin in all tissues (P0) and that of keratin 5-Cre conditional plectin-knockout mice (K5-Cre/cKO), where plectin deficiency is restricted to skin tissue (Ackerl et al, 2007)
Compromised barrier function of cell monolayers formed ex vivo by plectin-deficient endothelial cells Haemorrhagic blister formation in P0 mice is suggestive of increased fragility and leakiness of the vasculature
Summary
Weakened endothelial junctions lead to increased permeability and compromised vascular integrity causing haemorrhage, brain and pulmonary oedema, acute respiratory distress syndrome and increased susceptibility to stress induced injury (Maniatis and Orfanos, 2008). It has been shown that increased actin-driven contractility generates. Received 24 March 2015; Accepted 1 October 2015 tension that pulls cells away from each other, creating intercellular gaps and increasing permeability (Dudek and Garcia, 2001). This condition can be evoked upon thrombin, histamine, aldosterone release and, mechanically, upon stretch (Dejana et al, 2009; Shasby et al, 2002). Cytoskeleton integrity based on the balanced interplay of its components is emerging as key determinant of endothelial barrier function
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
