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Mechanosensing and Mechanoregulation of Endothelial Cell Functions

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ABSTRACT

Vascular endothelial cells (ECs) form a semiselective barrier for macromolecules and cell elements regulated by dynamic interactions between cytoskeletal elements and cell adhesion complexes. ECs also participate in many other vital processes including innate immune reactions, vascular repair, secretion, and metabolism of bioactive molecules. Moreover, vascular ECs represent a unique cell type exposed to continuous, time‐dependent mechanical forces: different patterns of shear stress imposed by blood flow in macrovasculature and by rolling blood cells in the microvasculature; circumferential cyclic stretch experienced by the arterial vascular bed caused by heart propulsions; mechanical stretch of lung microvascular endothelium at different magnitudes due to spontaneous respiration or mechanical ventilation in critically ill patients. Accumulating evidence suggests that vascular ECs contain mechanosensory complexes, which rapidly react to changes in mechanical loading, process the signal, and develop context‐specific adaptive responses to rebalance the cell homeostatic state. The significance of the interactions between specific mechanical forces in the EC microenvironment together with circulating bioactive molecules in the progression and resolution of vascular pathologies including vascular injury, atherosclerosis, pulmonary edema, and acute respiratory distress syndrome has been only recently recognized. This review will summarize the current understanding of EC mechanosensory mechanisms, modulation of EC responses to humoral factors by surrounding mechanical forces (particularly the cyclic stretch), and discuss recent findings of magnitude‐specific regulation of EC functions by transcriptional, posttranscriptional and epigenetic mechanisms using ‐omics approaches. We also discuss ongoing challenges and future opportunities in developing new therapies targeting dysregulated mechanosensing mechanisms to treat vascular diseases. © 2019 American Physiological Society. Compr Physiol 9:873‐904, 2019.

Figure 1. Figure 1. Mehcanoreceptors and sensors that regulate endothelial responses to biomechanical stimuli. Mechanosensors are distributed throughout the endothelium to sense and convert biomechanical cures (cyclic stretch, extracellular matrix stiffness, and fluid shear stress) into biological signaling. We systematically discussed the molecular identify of the putative mechanosensors in vascular endothelium in this review article. Moreover, mechanosensitive signaling pathways in vascular endothelium were also comprehensively described. Briefly, mechanical forces are transmitted and distributed throughout the endothelial cells via cilia, glycocalyx, cytoskeletal elements, nucleus, adhesion junctions, focal adhesions, and extracellular matrix. For instance, glycocalyx and cilia at the luminal surface can be deformed by mechanical load to trigger activation of ion channels, G‐protein‐coupled receptors, and calcium signaling. Force imbalance at cell‐cell contacts and cytoskeletal strain are transmitted to intracellular junctional protein complexes such as tight junctions, adhesion junctions, and gap junctions, leading to conformational changes of PECAM‐1 and α‐catenin, activation of Rho family of GTPases (Rho, RAc, and Cdc42) and recruitment of vinculin that trigger intracellular biochemical signals such as activation of src‐family kinase, PI3‐kinase, and MAP kinase. Cytoskeletal forces and extracellular stuffiness are also sensed by focal adhesions that are complex structures of large macromolecular assembles. For instance, transmembrane integrins that bind to extracellular matrix (ECM) can serve as a focus for force transmission and deformation to activate focal adhesion kinase (FAK), src‐family kinase, and small GTPase, leading to regulation of transcription factors YAP/TAZ, JNK, and MRTFs. The nucleus has emerged as an important cellular mechanosensor. External mechanical forces can be transmitted to the nucleus through cytoskeletons resulting in nuclear deformation and consequent changes of nuclear envelope structure and chromatin architecture.


Figure 1. Mehcanoreceptors and sensors that regulate endothelial responses to biomechanical stimuli. Mechanosensors are distributed throughout the endothelium to sense and convert biomechanical cures (cyclic stretch, extracellular matrix stiffness, and fluid shear stress) into biological signaling. We systematically discussed the molecular identify of the putative mechanosensors in vascular endothelium in this review article. Moreover, mechanosensitive signaling pathways in vascular endothelium were also comprehensively described. Briefly, mechanical forces are transmitted and distributed throughout the endothelial cells via cilia, glycocalyx, cytoskeletal elements, nucleus, adhesion junctions, focal adhesions, and extracellular matrix. For instance, glycocalyx and cilia at the luminal surface can be deformed by mechanical load to trigger activation of ion channels, G‐protein‐coupled receptors, and calcium signaling. Force imbalance at cell‐cell contacts and cytoskeletal strain are transmitted to intracellular junctional protein complexes such as tight junctions, adhesion junctions, and gap junctions, leading to conformational changes of PECAM‐1 and α‐catenin, activation of Rho family of GTPases (Rho, RAc, and Cdc42) and recruitment of vinculin that trigger intracellular biochemical signals such as activation of src‐family kinase, PI3‐kinase, and MAP kinase. Cytoskeletal forces and extracellular stuffiness are also sensed by focal adhesions that are complex structures of large macromolecular assembles. For instance, transmembrane integrins that bind to extracellular matrix (ECM) can serve as a focus for force transmission and deformation to activate focal adhesion kinase (FAK), src‐family kinase, and small GTPase, leading to regulation of transcription factors YAP/TAZ, JNK, and MRTFs. The nucleus has emerged as an important cellular mechanosensor. External mechanical forces can be transmitted to the nucleus through cytoskeletons resulting in nuclear deformation and consequent changes of nuclear envelope structure and chromatin architecture.

 

Teaching Material

Y. Fang, D. Wu, K. G. Birukov. Mechanosensing and Mechanoregulation of Endothelial Cell Functions. Compr Physiol 9: 2019, 873-904.

Didactic Synopsis

Major Teaching Points:

  • Cyclic stretch due to autonomous breathing is important in maintaining normal endothelial functions and the homeostasis of pulmonary circulation.
  • Endothelial cells respond to increased mechanical strain associated with mechanical ventilation by promoting inflammation, adhesion, and contractility leading to vascular dysfunction and pulmonary disorders.
  • A cohort of mechano-sensors has been proposed to mediate mechanotransmission and mechanotransduction in vascular endothelium.
    1. Mechanotransmission: External forces due to cyclic stretch and shear stress are loaded onto the endothelium, leading to internal tensional changes opposing the external forces. Externally applied forces are transmitted and distributed throughout the endothelial cells via cilia, glycocalyx, cytoskeletal elements, nucleus, adhesion junctions, focal adhesions, and extracellular matrix.
    2. Mechanotransduction: Transmitted mechanical forces at mechano-transduction sites alter the biochemical activities of specialized mechanosensory molecules resulting in cellular responses. Endothelial cells respond to changes of tension by activating or inactivating signaling pathways mediated by small GTPase, reactive oxygen species, tyrosine kinases, transcription factors, and non-coding RNAs.

Molecular insights related to stretch-sensing mechanisms in vascular endothelium may lead to new therapies treating pulmonary vascular diseases.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1 Teaching Points: Mechano-receptors and sensors that regulate endothelial responses to biomechanical stimuli. Mechanosensors are distributed throughout the endothelium to sense and convert biomechanical cures (cyclic stretch, extracellular matrix stiffness, and fluid shear stress) into biological signaling. We systemically discussed the molecular identify of the putative mechano-sensors in vascular endothelium in this review article. Moreover, mechano-sensitive signaling pathways in vascular endothelium were also comprehensively described. Briefly, mechanical forces are transmitted and distributed throughout the endothelial cells via cilia, glycocalyx, cytoskeletal elements, nucleus, adhesion junctions, focal adhesions, and extracellular matrix. For instance, glycocalyx and cilia at the luminal surface can be deformed by mechanical load to trigger activation of ion channels, G-protein-coupled receptors, and calcium signaling. Force imbalance at cell–cell contacts and cytoskeletal strain are transmitted to intracellular junctional protein complexes such as tight junctions, adhesion junctions, and gap junctions, leading to conformational changes of PECAM-1 and α-catenin, activation of Rho family of GTPases (Rho, RAc, and Cdc42) and recruitment of vinculin that trigger intracellular biochemical signals such as activation of src-family kinase, PI3-kinase, and MAP kinase. Cytoskeletal forces and extracellular stuffiness are also sensed by focal adhesions that are complex structures of large macromolecular assembles. For instance, transmembrane integrins that binds to extracellular matrix (ECM) can serve as a focus for force transmission and deformation to activate focal adhesion kinase (FAK), src-family kinase, and small GTPase, leading to regulation of transcription factors YAP/TAZ, JNK, and MRTFs. The nucleus has emerged as an important cellular mechanosensor. External mechanical forces can be transmitted to the nucleus through cytoskeletons resulting in nuclear deformation and consequent changes of nuclear envelope structure and chromatin architecture.

 


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How to Cite

Yun Fang, David Wu, Konstantin G. Birukov. Mechanosensing and Mechanoregulation of Endothelial Cell Functions. Compr Physiol 2019, 9: 873-904. doi: 10.1002/cphy.c180020