Lack of Primary Cilia Primes Shear-Induced Endothelial-to-Mesenchymal Transition
Open accessAbstract
Rationale: Primary cilia are cellular protrusions that serve as mechanosensors for fluid flow. In endothelial cells (ECs), they function by transducing local blood flow information into functional responses, such as nitric oxide production and initiation of gene expression. Cilia are present on ECs in areas of low or disturbed flow and absent in areas of high flow. In the embryonic heart, high-flow regime applies to the endocardial cushion area, and the absence of cilia here coincides with the process of endothelial-to-mesenchymal transition (EndoMT). Objective: In this study, we investigated the role of the primary cilium in defining the responses of ECs to fluid shear stress and in EndoMT. Methods and Results: Nonciliated mouse embryonic ECs with a mutation in Tg737/Ift88 were used to compare the response to fluid shear stress to that of ciliated ECs. In vitro, nonciliated ECs undergo shear-induced EndoMT, which is accompanied by downregulation of Klf4. This Tgfβ/Alk5-dependent transformation is prevented by blocking Tgfβ signaling, overexpression of Klf4, or rescue of the primary cilium. In the hearts of Tg737 orpk/orpk embryos, Tgfβ/Alk5 signaling was activated in areas in which ECs would normally be ciliated but now lack cilia because of the mutation. In these areas, ECs show increased Smad2 phosphorylation and expression of α-smooth muscle actin. Conclusions: This study demonstrates the central role of primary cilia in rendering ECs prone to shear-induced activation of Tgfβ/Alk5 signaling and EndoMT and thereby provides a functional link between primary cilia and flow-related endothelial performance.
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Endothelial primary cilia function as flow sensors in the vasculature and contribute to blood-brain barrier integrity, counteract endothelial-to-mesenchymal transition in a process associated with reduced canonical TGFβ signaling in the endocardial cushion area, and cooperate with BMP signaling to stabilize vessel connections in the developing mouse retina.
“Further, endothelial primary cilia, which function as flow sensors in the vasculature and contribute to blood–brain barrier integrity 276–279, counteract endothelial-to-mesenchymal transition in a process that is associated with reduced canonical TGFβ signalling in the endocardial cushion area 280, whereas endothelial primary cilia cooperate with BMP signalling to stabilize vessel connections in”
From Cellular signalling by primary cilia in development, organ function and disease (2019) · cites this paper as [279]
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- Authors
- Egorova, A. D., Khedoe, P. P. S. J., Goumans, M.-J. T. H., Yoder, B. K., Nauli, S. M., ten Dijke, P., Poelmann, R. E., & Hierck, B. P.
- Affiliations
- Leiden University Medical Center (NL)
- From the Departments of Anatomy and Embryology (A.D.E., P.P.S.J.K., R.E.P., B.P.H.) and Molecular Cell Biology and Center for Biomedical Genetics (M.-J.T.H.G., P.t.D.), Leiden University Medical Center, The Netherlands; Department of Cell Biology (B.K.Y.), University of Alabama at Birmingham; and Pharmacology and Medicine (S.M.N.), College of Pharmacy and Medicine, University of Toledo, Ohio. Present address for P.P.S.J.K.: Department of Pulmonology, Leiden University Medical Center, The Netherlands.
- ORCID
- Venue
- Circulation Research
- Published
- 2011-04-29
- Volume
- 108
- Issue
- 9
- Pages
- 1093-1101
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- PMC
- PMC3094764
- OpenAlex
- W2111090017
- Cited by
- 195
- References
- 48
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 8 · 2023: 11 · 2022: 7 · 2021: 14 · 2020: 9 · 2019: 18 · 2018: 17 · 2017: 16 · 2016: 16 · 2015: 15 · 2014: 14 · 2013: 9 · 2012: 17
- FWCI
- 9.98
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Chapman University Digital Commons (Chapman University) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Funders
- Universiteit Leiden
- Leids Universitair Medisch Centrum
- National Institute of Diabetes and Digestive and Kidney Diseases (DK080640, R01DK080640, P30DK074038)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- primary cilia, endothelial-to-mesenchymal transition, fluid shear stress, endothelial cells, KLF4, endocardial cushion, Smad2 phosphorylation, alpha-smooth muscle actin, mechanosensing, embryonic heart development
- MeSH terms
- Receptor, Transforming Growth Factor-beta Type I, Kruppel-Like Factor 4, Animals, Cell Differentiation, Cilia, Gene Expression Regulation, Mesoderm, Mice, Mutant Strains, Stress, Mechanical, Protein Serine-Threonine Kinases, Receptors, Transforming Growth Factor beta, Tumor Suppressor Proteins, Mechanotransduction, Cellular, Endothelial Cells, Mice, Kruppel-Like Transcription Factors, Smad2 Protein, Epithelial-Mesenchymal Transition
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