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Shear stress induces G?q/11 activation independently of G protein-coupled receptor activation in endothelial cells.

ABSTRACT: Mechanochemical signal transduction occurs when mechanical forces, such as fluid shear stress, are converted into biochemical responses within the cell. The molecular mechanisms by which endothelial cells (ECs) sense/transduce shear stress into biological signals, including the nature of the mechanosensor, are still unclear. G proteins and G protein-coupled receptors (GPCRs) have been postulated independently to mediate mechanotransduction. In this study, we used in situ proximity ligation assay (PLA) to investigate the role of a specific GPCR/G?q/11 pair in EC shear stress-induced mechanotransduction. We demonstrated that sphingosine 1-phosphate (S1P) stimulation causes a rapid dissociation at 0.5 min of G?q/11 from its receptor S1P3, followed by an increased association within 2 min of GPCR kinase-2 (GRK2) and ?-arrestin-1/2 with S1P3 in human coronary artery ECs, which are consistent with GPCR/G?q/11 activation and receptor desensitization/internalization. The G protein activator AlF4 resulted in increased dissociation of G?q/11 from S1P3, but no increase in association between S1P3 and either GRK2 or ?-arrestin-1/2. The G protein inhibitor guanosine 5'-(?-thio) diphosphate (GDP-?-S) and the S1P3 antagonist VPC23019 both prevented S1P-induced activation. Shear stress also caused the rapid activation within 7 s of S1P3/G?q/11 There were no increased associations between S1P3 and GRK2 or S1P3 and ?-arrestin-1/2 until 5 min. GDP-?-S, but not VPC23019, prevented dissociation of G?q/11 from S1P3 in response to shear stress. Shear stress did not induce rapid dephosphorylation of ?-arrestin-1 or rapid internalization of S1P3, indicating no GPCR activation. These findings suggest that G?q/11 participates in the sensing/transducing of shear stress independently of GPCR activation in ECs.

SUBMITTER: Dela Paz NG

PROVIDER: S-EPMC5407018 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Shear stress induces Gα<sub>q/11</sub> activation independently of G protein-coupled receptor activation in endothelial cells.

Dela Paz Nathaniel G NG Melchior Benoît B Frangos John A JA

American journal of physiology. Cell physiology 20170201 4

Mechanochemical signal transduction occurs when mechanical forces, such as fluid shear stress, are converted into biochemical responses within the cell. The molecular mechanisms by which endothelial cells (ECs) sense/transduce shear stress into biological signals, including the nature of the mechanosensor, are still unclear. G proteins and G protein-coupled receptors (GPCRs) have been postulated independently to mediate mechanotransduction. In this study, we used in situ proximity ligation assay ...[more]

PMID: 28148497

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Project description:The monolayer of cells that line both the heart and the entire vasculature is the endothelial cell (EC). These cells respond to external and internal signals, producing a wide array of primary or secondary messengers involved in coagulation, vascular tone, inflammation, and cell-to-cell signaling. Endothelial cell activation is the process by which EC changes from a quiescent cell phenotype, which maintains cellular integrity, antithrombotic, and anti-inflammatory properties, to a phenotype that is prothrombotic, pro-inflammatory, and permeable, in addition to repair and leukocyte trafficking at the site of injury or infection. Pathological activation of EC leads to increased vascular permeability, thrombosis, and an uncontrolled inflammatory response that leads to endothelial dysfunction. This pathological activation can be observed during ischemia reperfusion injury (IRI) and sepsis. Shear stress (SS) and pulsatile shear stress (PSS) are produced by mechanical frictional forces of blood flow and contraction of the heart, respectively, and are well-known mechanical signals that affect EC function, morphology, and gene expression. PSS promotes EC homeostasis and cardiovascular health. The archetype of inducing PSS is exercise (i.e., jogging, which introduces pulsations to the body as a function of the foot striking the pavement), or mechanical devices which induce external pulsations to the body (Enhanced External Pulsation (EECP), Whole-body vibration (WBV), and Whole-body periodic acceleration (WBPA aka pGz)). The purpose of this narrative review is to focus on the aforementioned noninvasive methods to increase PSS, review how each of these modify specific diseases that have been shown to induce endothelial activation and microcirculatory dysfunction (Ischemia reperfusion injury-myocardial infarction and cardiac arrest and resuscitation), sepsis, and lipopolysaccharide-induced sepsis syndrome (LPS)), and review current evidence and insight into how each may modify endothelial activation and how these may be beneficial in the acute and chronic setting of endothelial activation and microvascular dysfunction.

Dataset Information

Shear stress induces G?q/11 activation independently of G protein-coupled receptor activation in endothelial cells.

Publications

Shear stress induces Gα<sub>q/11</sub> activation independently of G protein-coupled receptor activation in endothelial cells.

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