Abstract:Mechanosensitive ion channels are implicated in the biology of touch, pain, hearing and vascular reactivity; however, the identity of these ion channels and the molecular basis of their activation is poorly understood. We previously found that transient receptor potential vanilloid 4 (TRPV4) is a receptor operated ion channel that is sensitised and activated by mechanical stress. Here, we investigated the effects of mechanical stimulation on TRPV4 localisation and activation in native and recombinant TRPV4-exp… Show more
“…Finally, it is already long known that shear stress induces currents across the plasma membrane of endothelial cells, for which mechanosensitive ion channels are responsible [71–73]. Of these mechano-channels, the endothelial-expressed transient receptor potential cation channel subfamily V member 4 (TRPV4) has been recently reported to be presented at higher levels in response to flow [74], and to interact with β-catenin at cell–cell junctions [75, 76]. This hints at a potential role for cell–cell junctions in Ca 2+ -dependent signaling during adaptation to flow-derived forces.Fig.…”
Section: Flow Mechanosensing: Roles Of Pecam-1 and Ve-cadherinmentioning
The vasculature is one of the most dynamic tissues that encounter numerous mechanical cues derived from pulsatile blood flow, blood pressure, activity of smooth muscle cells in the vessel wall, and transmigration of immune cells. The inner layer of blood and lymphatic vessels is covered by the endothelium, a monolayer of cells which separates blood from tissue, an important function that it fulfills even under the dynamic circumstances of the vascular microenvironment. In addition, remodeling of the endothelial barrier during angiogenesis and trafficking of immune cells is achieved by specific modulation of cell–cell adhesion structures between the endothelial cells. In recent years, there have been many new discoveries in the field of cellular mechanotransduction which controls the formation and destabilization of the vascular barrier. Force-induced adaptation at endothelial cell–cell adhesion structures is a crucial node in these processes that challenge the vascular barrier. One of the key examples of a force-induced molecular event is the recruitment of vinculin to the VE-cadherin complex upon pulling forces at cell–cell junctions. Here, we highlight recent advances in the current understanding of mechanotransduction responses at, and derived from, endothelial cell–cell junctions. We further discuss their importance for vascular barrier function and remodeling in development, inflammation, and vascular disease.
“…Finally, it is already long known that shear stress induces currents across the plasma membrane of endothelial cells, for which mechanosensitive ion channels are responsible [71–73]. Of these mechano-channels, the endothelial-expressed transient receptor potential cation channel subfamily V member 4 (TRPV4) has been recently reported to be presented at higher levels in response to flow [74], and to interact with β-catenin at cell–cell junctions [75, 76]. This hints at a potential role for cell–cell junctions in Ca 2+ -dependent signaling during adaptation to flow-derived forces.Fig.…”
Section: Flow Mechanosensing: Roles Of Pecam-1 and Ve-cadherinmentioning
The vasculature is one of the most dynamic tissues that encounter numerous mechanical cues derived from pulsatile blood flow, blood pressure, activity of smooth muscle cells in the vessel wall, and transmigration of immune cells. The inner layer of blood and lymphatic vessels is covered by the endothelium, a monolayer of cells which separates blood from tissue, an important function that it fulfills even under the dynamic circumstances of the vascular microenvironment. In addition, remodeling of the endothelial barrier during angiogenesis and trafficking of immune cells is achieved by specific modulation of cell–cell adhesion structures between the endothelial cells. In recent years, there have been many new discoveries in the field of cellular mechanotransduction which controls the formation and destabilization of the vascular barrier. Force-induced adaptation at endothelial cell–cell adhesion structures is a crucial node in these processes that challenge the vascular barrier. One of the key examples of a force-induced molecular event is the recruitment of vinculin to the VE-cadherin complex upon pulling forces at cell–cell junctions. Here, we highlight recent advances in the current understanding of mechanotransduction responses at, and derived from, endothelial cell–cell junctions. We further discuss their importance for vascular barrier function and remodeling in development, inflammation, and vascular disease.
“…For example, when contact forces are initiated in joints during running there is an immediate increase in the fluid pressure due to tissue compression, which causes the fluid to flow out of the ECM, generating shear stress and frictional drag on the matrix . Shear stress has been shown to sensitize TRPV4 activation in vascular endothelial cells, by recruiting TRPV4 to the plasma membrane . Changes of 10%‐15% in the height of chondrocytes have been measured in response to mechanical inputs, though forces will be dispersed differently in each cartilage zone, resulting in zone‐dependent shape changes in the chondron .…”
Section: Relating In Vitro Measurements Of Trpv4 and Piezo1 Activatiomentioning
confidence: 99%
“…47,50 Shear stress has been shown to sensitize TRPV4 activation in vascular endothelial cells, by recruiting TRPV4 to the plasma membrane. 51 Changes of 10%-15% in the height of chondrocytes have been measured in response to mechanical inputs, 52,53 though forces will be dispersed differently in each cartilage zone, resulting in zone-dependent shape changes in the chondron. 54…”
Section: Rel Ating In Vitro Me a Surements Of Trpv4 And Pie Zo1 Ac mentioning
Cartilage tissue lines the joints of mammals, helping to lubricate joint movement and distribute mechanical loads. This tissue is comprised of isolated cells known as chondrocytes which are embedded in an extracellular matrix. Chondrocytes produce and maintain the cartilage by sensing and responding to changing mechanical loads. Mechanosensitive ion channels have been implicated in chondrocyte mechanotransduction and recent studies have shown that both PIEZO1 and TRPV4 can be activated by mechanical stimuli in these cells. The 2 channels mediate separate but overlapping mechanoelectrical transduction pathways, PIEZO1 in response to stretch and substrate deflections and TRPV4 in response to substrate deflections alone. These distinct pathways of mechanoelectrical transduction suggest a mechanism by which chondrocytes can distinguish between different stimuli that arise in their complex mechanical environment.
“…More recently, it has been demonstrated that laminar flow- and TRPV4 agonist-induced vasodilation was impaired in aged rat mesenteric arteries, which was restored by lentivirus-mediated TRPV4 overexpression [18]. Laminar flow also sensitizes the response of TRPV4 to GSK1016790A by promoting the trafficking of TRPV4 from intracellular compartments to the plasma membrane [19]. However, it remains unknown whether pharmacological activation of TRPV4 by GSK1016790A can elicits laminar flow signaling events and prevents the development of atherosclerosis.…”
TRPV4 ion channel mediates vascular mechanosensitivity and vasodilation. Here, we sought to explore whether non-mechanical activation of TRPV4 could limit vascular inflammation and atherosclerosis. We found that GSK1016790A, a potent and specific small-molecule agonist of TRPV4, induces the phosphorylation and activation of eNOS partially through the AMPK pathway. Moreover, GSK1016790A inhibited TNF-α-induced monocyte adhesion to human endothelial cells. Mice given GSK1016790A showed increased phosphorylation of eNOS and AMPK in the aorta and decreased leukocyte adhesion to TNF-α-inflamed endothelium. Importantly, oral administration of GSK1016790A reduced atherosclerotic plaque formation in ApoE deficient mice fed a Western-type diet. Together, the present study suggests that pharmacological activation of TRPV4 may serve as a potential therapeutic approach to treat atherosclerosis.
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