Substrate stiffness modulates endothelial cell function via the YAP-Dll4-Notch1 pathway. 2021

Eri Matsuo, and Takayuki Okamoto, and Atsushi Ito, and Eiji Kawamoto, and Kunihiro Asanuma, and Koichiro Wada, and Motomu Shimaoka, and Motoshi Takao, and Akira Shimamoto
Department of Thoracic and Cardiovascular Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu-city, Mie, 514-8507, Japan; Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu-city, Mie, 514-8507, Japan.

Endothelial cells adapt their functions as a consequence of sensing extracellular substrate stiffness; these alterations allow them to maintain their vascular structure and function. Substrate stiffness-mediated yes-associated protein 1 (YAP) activation plays an important role in mechano-transduction and pro-angiogenic phenotype of endothelial cells, and Delta-like ligand 4 (Dll4)-Notch1 signaling is closely related to angiogenesis; however, the impact of substrate stiffness-mediated interrelation of these pathways on endothelial cell functions remains elusive. We confirmed that endothelial cells on softer substrates not only elongate cellular aspects but also attenuate YAP activation compared to cells on stiffer substrates. Endothelial cells on softer substrates also upregulate the vascular endothelial growth factor receptor 1 (VEGFR1) and VEGFR2 mRNA expression that is enhanced by VEGF stimulation. We determined that endothelial cells on softer substrates increased Dll4 expression, but not Notch1 expression, via YAP signaling. Moreover, endothelial cells on soft substrates induced not only VEGFRs upregulation but also suppression of pro-inflammatory interleukin-6 and plasminogen activator inhibitor-1 mRNA expression and the facilitation of anti-coagulant thrombomodulin and pro-coagulant tissue factor mRNA expression. Our results suggest that endothelial cells activate the YAP-Dll4-Notch signaling pathway in response to substrate stiffness and dictate cellular function.

UI MeSH Term Description Entries
D009389 Neovascularization, Pathologic A pathologic process consisting of the proliferation of blood vessels in abnormal tissues or in abnormal positions. Angiogenesis, Pathologic,Angiogenesis, Pathological,Neovascularization, Pathological,Pathologic Angiogenesis,Pathologic Neovascularization,Pathological Angiogenesis,Pathological Neovascularization
D002135 Calcium-Binding Proteins Proteins to which calcium ions are bound. They can act as transport proteins, regulator proteins, or activator proteins. They typically contain EF HAND MOTIFS. Calcium Binding Protein,Calcium-Binding Protein,Calcium Binding Proteins,Binding Protein, Calcium,Binding Proteins, Calcium,Protein, Calcium Binding,Protein, Calcium-Binding
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000091102 YAP-Signaling Proteins Signal transducing adaptor proteins that were initially identified by their association with YES PROTO-ONCOGENE PROTEIN. They are downstream components of the HIPPO-SIGNALING PATHWAY, and act as transcriptional co-activators for TEAD TRANSCRIPTION FACTORS. YAP Intracellular Signaling Proteins,Yes-Associated Proteins,YAP Signaling Proteins,Yes Associated Proteins
D014157 Transcription Factors Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. Transcription Factor,Factor, Transcription,Factors, Transcription
D042783 Endothelial Cells Highly specialized EPITHELIAL CELLS that line the HEART; BLOOD VESSELS; and lymph vessels, forming the ENDOTHELIUM. They are polygonal in shape and joined together by TIGHT JUNCTIONS. The tight junctions allow for variable permeability to specific macromolecules that are transported across the endothelial layer. Capillary Endothelial Cells,Lymphatic Endothelial Cells,Vascular Endothelial Cells,Capillary Endothelial Cell,Cell, Capillary Endothelial,Cell, Endothelial,Cell, Lymphatic Endothelial,Cell, Vascular Endothelial,Cells, Capillary Endothelial,Cells, Endothelial,Cells, Lymphatic Endothelial,Cells, Vascular Endothelial,Endothelial Cell,Endothelial Cell, Capillary,Endothelial Cell, Lymphatic,Endothelial Cell, Vascular,Endothelial Cells, Capillary,Endothelial Cells, Lymphatic,Endothelial Cells, Vascular,Lymphatic Endothelial Cell,Vascular Endothelial Cell
D048868 Adaptor Proteins, Signal Transducing A broad category of carrier proteins that play a role in SIGNAL TRANSDUCTION. They generally contain several modular domains, each of which having its own binding activity, and act by forming complexes with other intracellular-signaling molecules. Signal-transducing adaptor proteins lack enzyme activity, however their activity can be modulated by other signal-transducing enzymes Signal Transducing Adaptor Proteins
D051881 Receptor, Notch1 A notch receptor that interacts with a variety of ligands and regulates SIGNAL TRANSDUCTION PATHWAYS for multiple cellular processes. It is widely expressed during EMBRYOGENESIS and is essential for EMBRYONIC DEVELOPMENT. Notch1 Receptor,Notch1 Protein
D018919 Neovascularization, Physiologic The development of new BLOOD VESSELS during the restoration of BLOOD CIRCULATION during the healing process. Angiogenesis, Physiologic,Angiogenesis, Physiological,Neovascularization, Physiological,Physiologic Angiogenesis,Physiologic Neovascularization,Physiological Angiogenesis,Physiological Neovascularization
D036341 Intercellular Signaling Peptides and Proteins Regulatory proteins and peptides that are signaling molecules involved in the process of PARACRINE COMMUNICATION. They are generally considered factors that are expressed by one cell and are responded to by receptors on another nearby cell. They are distinguished from HORMONES in that their actions are local rather than distal. Growth Factor,Growth Factors,Paracrine Peptide Factors,Paracrine Protein Factors,Factor, Growth,Factors, Growth,Peptide Factors, Paracrine

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