Proceedings of the National Academy of Sciences - PNAS, 2020-05, Vol.117 (18), p.9896-9905
2020
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- Autor(en) / Beteiligte
- Titel
- Matrix mechanotransduction mediated by thrombospondin-1/integrin/YAP in the vascular remodeling
- Ist Teil von
- Proceedings of the National Academy of Sciences - PNAS, 2020-05, Vol.117 (18), p.9896-9905
- Ort / Verlag
- United States: National Academy of Sciences
- Erscheinungsjahr
- 2020
- Quelle
- Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
- Beschreibungen/Notizen
- The extracellular matrix (ECM) initiates mechanical cues that activate intracellular signaling through matrix–cell interactions. In blood vessels, additional mechanical cues derived from the pulsatile blood flow and pressure play a pivotal role in homeostasis and disease development. Currently, the nature of the cues from the ECM and their interaction with the mechanical microenvironment in large blood vessels to maintain the integrity of the vessel wall are not fully understood. Here, we identified the matricellular protein thrombospondin-1 (Thbs1) as an extracellular mediator of matrix mechanotransduction that acts via integrin αvβ1 to establish focal adhesions and promotes nuclear shuttling of Yesassociated protein (YAP) in response to high strain of cyclic stretch. Thbs1-mediated YAP activation depends on the small GTPase Rap2 and Hippo pathway and is not influenced by alteration of actin fibers. Deletion of Thbs1 in mice inhibited Thbs1/integrin β1/YAP signaling, leading to maladaptive remodeling of the aorta in response to pressure overload and inhibition of neointima formation upon carotid artery ligation, exerting context-dependent effects on the vessel wall. We thus propose a mechanism of matrix mechanotransduction centered on Thbs1, connecting mechanical stimuli to YAP signaling during vascular remodeling in vivo.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0027-8424eISSN: 1091-6490DOI: 10.1073/pnas.1919702117Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7211957
- Format
- –
- Schlagworte
- Actin, Adaptor Proteins, Signal Transducing - genetics, Adaptor Proteins, Signal Transducing - metabolism, Animals, Aorta, Aorta - growth & development, Aorta - metabolism, Biological Sciences, Blood flow, Blood pressure, Blood vessels, Carotid Arteries - growth & development, Carotid Arteries - metabolism, Carotid artery, Cell interactions, Cellular Microenvironment - genetics, Extracellular matrix, Extracellular Matrix - genetics, Extracellular Matrix - metabolism, Fibers, Focal Adhesions - genetics, Guanosine triphosphatases, Homeostasis, Humans, Integrin beta1 - genetics, Integrin beta1 - metabolism, Intracellular signalling, Mechanical stimuli, Mechanotransduction, Mechanotransduction, Cellular, Mice, Neointima - genetics, Neointima - metabolism, Protein-Serine-Threonine Kinases - genetics, Proteins, rap GTP-Binding Proteins - genetics, Signal Transduction - genetics, Signaling, Thrombospondin, Thrombospondin 1 - genetics, Thrombospondin 1 - metabolism, Transcription Factors - genetics, Transcription Factors - metabolism, Vascular Remodeling - genetics, Yes-associated protein