Primary cilia control endothelial permeability by regulating expression and location of junction proteins

Diagbouga, Mannekomba Roxane; Morel, Sandrine; Cayron, Anne F; Haemmerli, Julien; Georges, Marc; Hierck, Beerend P.; Allémann, Éric; Lemeille, Sylvain; Bijlenga, Philippe; Kwak, Brenda R.

doi:10.1093/cvr/cvab165

Cited by 12 publications

(21 citation statements)

References 42 publications

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“…Patients carrying a mutation of genes affecting the expression or function of primary cilia are more prone to develop IA than the general population ( 8 , 9 ). In a previous study ( 47 ), we showed that the wall of unruptured IAs from PKD patients contained less collagen than the ones of non-PKD patients. In addition, PKD IAs displayed a more degraded vascular wall phenotype comparable to what was observed in ruptured IAs.…”

Section: Discussionmentioning

confidence: 75%

Effect of Aneurysm and Patient Characteristics on Intracranial Aneurysm Wall Thickness

Acosta

Cayron

Dupuy

et al. 2021

Front. Cardiovasc. Med.

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Background: The circle of Willis is a network of arteries allowing blood supply to the brain. Bulging of these arteries leads to formation of intracranial aneurysm (IA). Subarachnoid hemorrhage (SAH) due to IA rupture is among the leading causes of disability in the western world. The formation and rupture of IAs is a complex pathological process not completely understood. In the present study, we have precisely measured aneurysmal wall thickness and its uniformity on histological sections and investigated for associations between IA wall thickness/uniformity and commonly admitted risk factors for IA rupture.Methods: Fifty-five aneurysm domes were obtained at the Geneva University Hospitals during microsurgery after clipping of the IA neck. Samples were embedded in paraffin, sectioned and stained with hematoxylin-eosin to measure IA wall thickness. The mean, minimum, and maximum wall thickness as well as thickness uniformity was measured for each IA. Clinical data related to IA characteristics (ruptured or unruptured, vascular location, maximum dome diameter, neck size, bottleneck factor, aspect and morphology), and patient characteristics [age, smoking, hypertension, sex, ethnicity, previous SAH, positive family history for IA/SAH, presence of multiple IAs and diagnosis of polycystic kidney disease (PKD)] were collected.Results: We found positive correlations between maximum dome diameter or neck size and IA wall thickness and thickness uniformity. PKD patients had thinner IA walls. No associations were found between smoking, hypertension, sex, IA multiplicity, rupture status or vascular location, and IA wall thickness. No correlation was found between patient age and IA wall thickness. The group of IAs with non-uniform wall thickness contained more ruptured IAs, women and patients harboring multiple IAs. Finally, PHASES and ELAPSS scores were positively correlated with higher IA wall heterogeneity.Conclusion: Among our patient and aneurysm characteristics of interest, maximum dome diameter, neck size and PKD were the three factors having the most significant impact on IA wall thickness and thickness uniformity. Moreover, wall thickness heterogeneity was more observed in ruptured IAs, in women and in patients with multiple IAs. Advanced medical imaging allowing in vivo measurement of IA wall thickness would certainly improve personalized management of the disease and patient care.

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Section: Discussionmentioning

confidence: 75%

Effect of Aneurysm and Patient Characteristics on Intracranial Aneurysm Wall Thickness

Acosta

Cayron

Dupuy

et al. 2021

Front. Cardiovasc. Med.

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“…For flow experiments, cells were seeded on 1% gelatin coated Ibidi μ-Slides VI 0.4 at 30.000 cells per channel and grown until confluence. Laminar shear stress of 2, 30, or 80 dyne/cm 2 was applied for 48 h using an Ibidi flow system as previously described ( Pfenniger et al, 2012 ; Denis et al, 2019 ; Diagbouga et al, 2021 ).…”

Section: Methodsmentioning

confidence: 99%

“…ECs are equipped with a multitude of potential shear stress sensors including membrane-associated molecules (e.g., ion channels, receptors, adhesion molecules), the glycocalyx and specific membrane microdomains such as caveolae and primary cilia ( Ando and Yamamoto, 2013 ; Kwak et al, 2014 ). We recently reported that the EC response to aneurysmal low WSS was dampened in ECs without primary cilium, leading to disorganized intercellular junctions and increased endothelial permeability ( Diagbouga et al, 2021 ). Altered endothelial function is supposed to be an important factor for the increased severity of IA disease observed in polycystic kidney disease (PKD) patients, a genetic disorder affecting primary cilia ( Cho et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Effects of Low and High Aneurysmal Wall Shear Stress on Endothelial Cell Behavior: Differences and Similarities

et al. 2021

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Background: Intracranial aneurysms (IAs) result from abnormal enlargement of the arterial lumen. IAs are mostly quiescent and asymptomatic, but their rupture leads to severe brain damage or death. As the evolution of IAs is hard to predict and intricates medical decision, it is essential to improve our understanding of their pathophysiology. Wall shear stress (WSS) is proposed to influence IA growth and rupture. In this study, we investigated the effects of low and supra-high aneurysmal WSS on endothelial cells (ECs).Methods: Porcine arterial ECs were exposed for 48 h to defined levels of shear stress (2, 30, or 80 dyne/cm2) using an Ibidi flow apparatus. Immunostaining for CD31 or γ-cytoplasmic actin was performed to outline cell borders or to determine cell architecture. Geometry measurements (cell orientation, area, circularity and aspect ratio) were performed on confocal microscopy images. mRNA was extracted for RNAseq analysis.Results: ECs exposed to low or supra-high aneurysmal WSS were more circular and had a lower aspect ratio than cells exposed to physiological flow. Furthermore, they lost the alignment in the direction of flow observed under physiological conditions. The effects of low WSS on differential gene expression were stronger than those of supra-high WSS. Gene set enrichment analysis highlighted that extracellular matrix proteins, cytoskeletal proteins and more particularly the actin protein family were among the protein classes the most affected by shear stress. Interestingly, most genes showed an opposite regulation under both types of aneurysmal WSS. Immunostainings for γ-cytoplasmic actin suggested a different organization of this cytoskeletal protein between ECs exposed to physiological and both types of aneurysmal WSS.Conclusion: Under both aneurysmal low and supra-high WSS the typical arterial EC morphology molds to a more spherical shape. Whereas low WSS down-regulates the expression of cytoskeletal-related proteins and up-regulates extracellular matrix proteins, supra-high WSS induces opposite changes in gene expression of these protein classes. The differential regulation in EC gene expression observed under various WSS translate into a different organization of the ECs’ architecture. This adaptation of ECs to different aneurysmal WSS conditions may affect vascular remodeling in IAs.

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“…In adult mice, primary cilia are particularly abundant in ECs of arterial regions experiencing low shear stress, a condition that is typically observed in wide-neck intracranial aneurysms. In the absence of primary cilia, ZO-1 expression levels are reduced, disorganizing intercellular junctions resulting in increased endothelial permeability [ 99 ].…”

Section: Cytoskeleton In Endothelial–mesenchymal Transitionmentioning

confidence: 99%

Cytoskeleton Reorganization in EndMT—The Role in Cancer and Fibrotic Diseases

Wawro

Sacewicz-Hofman

Sobierajska

2021

IJMS

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Chronic inflammation promotes endothelial plasticity, leading to the development of several diseases, including fibrosis and cancer in numerous organs. The basis of those processes is a phenomenon called the endothelial–mesenchymal transition (EndMT), which results in the delamination of tightly connected endothelial cells that acquire a mesenchymal phenotype. EndMT-derived cells, known as the myofibroblasts or cancer-associated fibroblasts (CAFs), are characterized by the loss of cell–cell junctions, loss of endothelial markers, and gain in mesenchymal ones. As a result, the endothelium ceases its primary ability to maintain patent and functional capillaries and induce new blood vessels. At the same time, it acquires the migration and invasion potential typical of mesenchymal cells. The observed modulation of cell shape, increasedcell movement, and invasion abilities are connected with cytoskeleton reorganization. This paper focuses on the review of current knowledge about the molecular pathways involved in the modulation of each cytoskeleton element (microfilaments, microtubule, and intermediate filaments) during EndMT and their role as the potential targets for cancer and fibrosis treatment.

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Primary cilia control endothelial permeability by regulating expression and location of junction proteins

Cited by 12 publications

References 42 publications

Effect of Aneurysm and Patient Characteristics on Intracranial Aneurysm Wall Thickness

Effect of Aneurysm and Patient Characteristics on Intracranial Aneurysm Wall Thickness

Effects of Low and High Aneurysmal Wall Shear Stress on Endothelial Cell Behavior: Differences and Similarities

Cytoskeleton Reorganization in EndMT—The Role in Cancer and Fibrotic Diseases

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