Intra-vessel heterogeneity establishes enhanced sites of macromolecular leakage downstream of laminin α5

Richards, Mark; Pal, Sagnik; Sjöberg, Elin; Martinsson, Pernilla; Venkatraman, Lakshmi; Claesson‐Welsh, Lena

doi:10.1016/j.celrep.2021.109268

Cited by 15 publications

(18 citation statements)

References 51 publications

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“…Here, intradermal administration of histamine elicited a similar leakage patterning as previously shown for VEGF-A, with leakage occurring only in vessels lacking apparent Cldn5 (BAC)-GFP expression (Figure 2Ai and ii and Movie 1). Interestingly, a population of Cldn5 (BAC)-GFP-negative vessels that failed to respond to histamine stimulation exists, highlighting the potential importance of factors other than Claudin5 that influence vessel susceptibility to stimulation (Figure 2Aiii) (Richards et al, 2021).…”

Section: Resultsmentioning

confidence: 99%

“…Outside of the CNS pericyte coverage is comparatively low, whether coverage differs between non-CNS vascular beds however is unknown. Barrier integrity may also be regulated by basement membrane components such as laminin α5, which enhances VE-Cadherin stability at cellcell junctions (Richards et al, 2021, Song et al, 2017). Similar to pericytes, basement membrane coverage differs between different vascular beds, as well as between vessel subtypes (Richards et al, 2021, Di Russo et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, a population of Cldn5(BAC)-GFP-negative vessels that failed to respond to histamine stimulation exists, highlighting the potential importance of factors other than Claudin5 that influence vessel susceptibility to stimulation (Figure 2Aiii) (Richards et al, 2021).…”

Section: Organotypic Regulation Of Barrier Integritymentioning

confidence: 99%

“…Outside of the CNS, Claudin5 is expressed to a lower degree, as are other TJ proteins such as Occludin (Scalise et al, 2021). Consequently, blood vessels outside of the CNS have a more permeable EC barrier, although EC permeability also differs greatly between these peripheral tissues and is inherently linked to the organ-specific function (Richards et al, 2021, Augustin and Koh, 2017). Furthermore, EC barrier integrity differs between vessel subtypes within these vascular beds (McDonald, 1994, Honkura et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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Claudin5 protects the peripheral endothelial barrier in an organ and vessel type-specific manner

Richards

Nwadozi

Pal

et al. 2022

Preprint

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The pathogenesis of numerous diseases is characterised by disruption of the junctions that form the endothelial cell (EC) barrier, the composition of which may differ greatly between organs. However, the expression level variability and precise contribution of different junctional proteins is poorly understood. Here, we focus on organs with continuous endothelium to identify structural and functional in vivo characteristics of the EC barrier. Assembly of multiple single-cell RNAseq datasets into a single integrated database revealed the variability in EC barrier patterning. Across tissues Claudin5 exhibited diminishing expression along the arteriovenous axis, which correlates with EC barrier integrity. Functional analysis identified tissue-specific differences in leakage patterning and response to agonist-induced leakage. We uncover that Claudin5 loss enhances agonist-induced leakage in an organotypic, vessel type-specific and size-selective manner in an inducible, EC-specific, knock-out mouse. Mechanistically, Claudin5 loss induces no change in junction ultrastructure but alters composition, with concomitant loss of zonula occludens-1 (ZO-1) expression and upregulation of VE-Cadherin. These findings uncover the organ-specific organisation of the EC barrier and distinct importance of Claudin5 in different vascular beds and will aid our ability to modify EC barrier stability in a targeted, organ-specific manner.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Organotypic Regulation Of Barrier Integritymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Claudin5 protects the peripheral endothelial barrier in an organ and vessel type-specific manner

Richards

Nwadozi

Pal

et al. 2022

Preprint

Self Cite

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“…Little is known on how TJ are disassembled when leakage is increased. In addition, pericytes and the basement membrane form additional barriers that must be disrupted for leakage to occur [12][13][14]. In addition to vascular barrier properties, cytokine/chemokine-derived cues present in the microenvironment operate on the leukocytes, stimulating their mobility and propensity to transmigrate [10].…”

Section: Introductionmentioning

confidence: 99%

Perspectives on Vascular Regulation of Mechanisms Controlling Selective Immune Cell Function in the Tumor Immune Response

Welsh

2022

IJMS

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The vasculature plays a major role in regulating the tumor immune cell response although the underlying mechanisms explaining such effects remain poorly understood. This review discusses current knowledge on known vascular functions with a viewpoint on how they may yield distinct immune responses. The vasculature might directly influence selective immune cell infiltration into tumors by its cell surface expression of cell adhesion molecules, expression of cytokines, cell junction properties, focal adhesions, cytoskeleton and functional capacity. This will alter the tumor microenvironment and unleash a plethora of responses that will influence the tumor’s immune status. Despite our current knowledge of numerous mechanisms operating, the field is underexplored in that few functions providing a high degree of specificity have yet been provided in relation to the enormous divergence of responses apparent in human cancers. Further exploration of this field is much warranted.

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Bicuspid aortic valve aortopathy is characterized by embryonic epithelial to mesenchymal transition and endothelial instability

et al. 2023

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Bicuspid aortic valve (BAV) is the most common congenital heart malformation frequently associated with ascending aortic aneurysm (AscAA). Epithelial to mesenchymal transition (EMT) may play a role in BAV-associated AscAA. The aim of the study was to investigate the type of EMT associated with BAV aortopathy using patients with a tricuspid aortic valve (TAV) as a reference. The state of the endothelium was further evaluated. Aortic biopsies were taken from patients undergoing open-heart surgery. Aortic intima/media miRNA and gene expression was analyzed using Affymetrix human transcriptomic array. Histological staining assessed structure, localization, and protein expression. Migration/proliferation was assessed using ORIS migration assay. We show different EMT types associated with BAV and TAV AscAA. Specifically, in BAV-associated aortopathy, EMT genes related to endocardial cushion formation were enriched. Further, BAV vascular smooth muscle cells were less proliferative and migratory. In contrast, TAV aneurysmal aortas displayed a fibrotic EMT phenotype with medial degenerative insults. Further, non-dilated BAV aortas showed a lower miRNA-200c-associated endothelial basement membrane LAMC1 expression and lower CD31 expression, accompanied by increased endothelial permeability indicated by increased albumin infiltration. Embryonic EMT is a characteristic of BAV aortopathy, associated with endothelial instability and vascular permeability of the non-dilated aortic wall. Key messages Embryonic EMT is a feature of BAV-associated aortopathy. Endothelial integrity is compromised in BAV aortas prior to dilatation. Non-dilated BAV ascending aortas are more permeable than aortas of tricuspid aortic valve patients.

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Intra-vessel heterogeneity establishes enhanced sites of macromolecular leakage downstream of laminin α5

Cited by 15 publications

References 51 publications

Claudin5 protects the peripheral endothelial barrier in an organ and vessel type-specific manner

Claudin5 protects the peripheral endothelial barrier in an organ and vessel type-specific manner

Perspectives on Vascular Regulation of Mechanisms Controlling Selective Immune Cell Function in the Tumor Immune Response

Bicuspid aortic valve aortopathy is characterized by embryonic epithelial to mesenchymal transition and endothelial instability

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