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

Cardiovascular Research, vol. 118, pp. 1583–1596

Abstract

AIMS: Wall shear stress (WSS) determines intracranial aneurysm (IA) development. Polycystic kidney disease (PKD) patients have a high IA incidence and risk of rupture. Dysfunction/absence of primary cilia in PKD endothelial cells (ECs) may impair mechano-transduction of WSS and favour vascular disorders. The molecular links between primary cilia dysfunction and IAs are unknown. METHODS AND RESULTS: Wild-type and primary cilia-deficient Tg737orpk/orpk arterial ECs were submitted to physiological (30 dynes/cm2) or aneurysmal (2 dynes/cm2) WSS, and unbiased transcriptomics were performed. Tg737orpk/orpk ECs displayed a fivefold increase in the number of WSS-responsive genes compared to wild-type cells. Moreover, we observed a lower trans-endothelial resistance and a higher endothelial permeability, which correlated with disorganized intercellular junctions in Tg737orpk/orpk cells. We identified ZO-1 as a central regulator of primary cilia-dependent endothelial junction integrity. Finally, clinical and histological characteristics of IAs from non-PKD and PKD patients were analysed. IAs in PKD patients were more frequently located in the middle cerebral artery (MCA) territory than in non-PKD patients. IA domes from the MCA of PKD patients appeared thinner with less collagen and reduced endothelial ZO-1 compared with IA domes from non-PKD patients. CONCLUSION: Primary cilia dampen the endothelial response to aneurysmal low WSS. In absence of primary cilia, ZO-1 expression levels are reduced, which disorganizes intercellular junctions resulting in increased endothelial permeability. This altered endothelial function may not only contribute to the severity of IA disease observed in PKD patients, but may also serve as a potential diagnostic tool to determine the vulnerability of IAs.

Authors 9

1. Mannekomba R. Diagbouga

   University of Geneva

   Affiliation as printed

   Department of Pathology and Immunology, University of Geneva, Rue Michel-Servet 1, CH-1211 Geneva, Switzerland

2. Sandrine Morel

   University of Geneva · University Hospital of Geneva

   Affiliation as printed

   Department of Pathology and Immunology, University of Geneva, Rue Michel-Servet 1, CH-1211 Geneva, Switzerland

   Neurosurgery Division, Department of Clinical Neurosciences, Geneva University Hospitals and University of Geneva, Rue Gabrielle-Perret-Gentil 4, CH-1211 Geneva, Switzerland

3. Anne F. Cayron

   University of Geneva

   Affiliation as printed

   Department of Pathology and Immunology, University of Geneva, Rue Michel-Servet 1, CH-1211 Geneva, Switzerland

   Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Rue Michel-Servet 1, CH-1211 Geneva, Switzerland

   School of Pharmaceutical Sciences, University of Geneva, Rue Michel-Servet 1, CH-1211 Geneva, Switzerland

4. Julien Haemmerli

   University of Geneva · University Hospital of Geneva

   Affiliation as printed

   Neurosurgery Division, Department of Clinical Neurosciences, Geneva University Hospitals and University of Geneva, Rue Gabrielle-Perret-Gentil 4, CH-1211 Geneva, Switzerland

5. Beerend P. Hierck Aachen Department of Anatomy and Embryology

   Leiden University Medical Center

   Affiliation as printed

   Department of Anatomy and Embryology, Leiden University Medical Center, Eindhovenweg 20, 2333ZC Leiden, the Netherlands

6. Éric Allémann

   University of Geneva

   Affiliation as printed

   Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Rue Michel-Servet 1, CH-1211 Geneva, Switzerland

   School of Pharmaceutical Sciences, University of Geneva, Rue Michel-Servet 1, CH-1211 Geneva, Switzerland

7. Sylvain Lemeille

   University of Geneva

   Affiliation as printed

   Department of Pathology and Immunology, University of Geneva, Rue Michel-Servet 1, CH-1211 Geneva, Switzerland

8. Philippe Bijlenga

   University of Geneva · University Hospital of Geneva

   Affiliation as printed

   Neurosurgery Division, Department of Clinical Neurosciences, Geneva University Hospitals and University of Geneva, Rue Gabrielle-Perret-Gentil 4, CH-1211 Geneva, Switzerland

9. Brenda Renata Kwak corresponding

   University of Geneva

   Affiliation as printed

   Department of Pathology and Immunology, University of Geneva, Rue Michel-Servet 1, CH-1211 Geneva, Switzerland