Cyclic stretch-induced thrombin generation by rat vascular smooth muscle cells is mediated by the integrin αvβ3 pathway

Mao, Xianqing; Said, Rose; Louis, Huguette; Max, Jean‐Pierre; Bourhim, Mustapha; Challande, Pascal; Wahl, Denis; Li, Zhenlin; Régnault, V.; Lacolley, Patrick

doi:10.1093/cvr/cvs274

Cited by 27 publications

(24 citation statements)

References 33 publications

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“…ERK1/2, p38 MAPK and Akt pathways are activated rapidly by stretch as early as several minutes after treatment [34], [35], and these pathways were reported to be associated with VSMC differentiation. ERK1/2 activation induced by sustained stretch contributed to increased VSMC proliferation and migration [36].…”

Section: Discussionmentioning

confidence: 99%

Mechanical Stretch Suppresses microRNA-145 Expression by Activating Extracellular Signal-Regulated Kinase 1/2 and Upregulating Angiotensin-Converting Enzyme to Alter Vascular Smooth Muscle Cell Phenotype

Song

et al. 2014

PLoS ONE

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Phenotype modulation of vascular smooth muscle cells (VSMCs) plays an important role in the pathogenesis of various vascular diseases, including hypertension and atherosclerosis. Several microRNAs (miRNAs) were found involved in regulating the VSMC phenotype with platelet-derived growth factor (PDGF) treatment, but the role of miRNAs in the mechanical stretch-altered VSMC phenotype is not clear. Here, we identified miR-145 as a major miRNA contributing to stretch-altered VSMC phenotype by miRNA array, quantitative RT-PCR and gain- and loss-of-function methods. Our data demonstrated that 16% stretch suppressed miR-145 expression, with reduced expression of contractile markers of VSMCs cultured on collagenI; overexpression of miR-145 could partially recover the expression in stretched cells. Serum response factor (SRF), myocardin, and Kruppel-like factor 4 (KLF4) are major regulators of the VSMC phenotype. The effect of stretch on myocardin and KLF4 protein expression was altered by miR-145 mimics, but SRF expression was not affected. In addition, stretch-activated extracellular signal-regulated kinase 1/2 (ERK1/2) and up-regulated angiotensin-converting enzyme (ACE) were confirmed to be responsible for the inhibition of miR-145 expression. Mechanical stretch inhibits miR-145 expression by activating the ERK1/2 signaling pathway and promoting ACE expression, thus modulating the VSMC phenotype.

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Section: Discussionmentioning

confidence: 99%

Mechanical Stretch Suppresses microRNA-145 Expression by Activating Extracellular Signal-Regulated Kinase 1/2 and Upregulating Angiotensin-Converting Enzyme to Alter Vascular Smooth Muscle Cell Phenotype

Song

et al. 2014

PLoS ONE

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“…26 We can anticipate a synergistic effect between anionic phospholipid membranes, TF, and integrin α v β 3 on increased thrombin generation in the SHR vascular wall because this integrin is the receptor for prothrombin in SMCs 27 and is involved in SMC-supported thrombin generation. 28 In this context, we would expect a difference in the incidence of thrombosis in Wistar and SHR and an exacerbation of the cellular effects of thrombin. The increase in thrombin generation within the vessel wall may modulate several wellknown vascular processes involved in hypertension, such as the regulation of vascular tone and the proliferation of SMCs, leading to increased pulse pressure and arterial stiffening.…”

Section: Discussionmentioning

confidence: 99%

Vascular Smooth Muscle Cells Are Responsible for a Prothrombotic Phenotype of Spontaneously Hypertensive Rat Arteries

Ait‐Aissa

Lagrange

Mohamadi

et al. 2015

ATVB

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Objective-The hypothesis that hypertension induces a hypercoagulable state arises from the complications associated with hypertension: stroke and myocardial infarction. Here, we determine whether hypertension causes changes in the thrombin-generating capacity of the vascular wall. Approach and Results-We used spontaneously hypertensive rats (SHR) compared with Wistar rats. The addition of thoracic aortic rings of SHR to a Wistar or SHR plasma pool resulted in a greater increase in thrombin generation compared with equivalent rings from Wistar. This increase occurred in 12-but not 5-week-old rats and was prevented by an angiotensin II-converting enzyme inhibitor, indicating that established hypertension is required to induce increased thrombin generation within the vessel wall. Whereas no difference was observed for endothelial cells, thrombin formation was higher on aortic smooth muscle cells (SMCs) from SHR than on those from Wistar. Exposure of negatively charged phospholipids was higher on SHR than on Wistar rings, as well as on cultured SMCs. Tissue factor activity was higher in SHR SMCs. Twelve-week-old SHR exhibited accelerated FeCl 3 -induced thrombus formation in carotid arteries, and the resulting occlusive thrombi were disaggregated by blockade of glycoprotein Ibα-von Willebrand factor interactions. SHR SMCs were more sensitive to thrombin-induced proliferation than Wistar SMCs. This effect was totally abolished by a protease-activated receptor 1 inhibitor. Conclusions-The prothrombotic phenotype of the SHR vessel wall was due to the ability of SMCs to support greater thrombin generation and resulted in accelerated occlusive thrombus formation after arterial injury, which was sensitive to glycoprotein Ibα-von Willebrand factor inhibitors. Ait Aissa et al Thrombin Generation in SHR Arteries 931One concern is that the function of the complex thrombin generation process is difficult to assess from estimates of its separate contributing elements. It would be preferable to estimate the overall activity of the hemostatic and thrombotic system and its relation with vascular function. This can be attempted by using a global in vitro test, such as the calibrated automated thrombogram, designed to explore the thrombin generation process under conditions as close as possible to those in vivo. This test has been shown to indicate a thrombotic tendency in several clinical settings, 11-14 which seems to be an independent predictor of acute ischemic stroke. 15The present study tests, in SHR, the hypothesis that changes in coagulation proteins and membrane phospholipid organization cause an increased thrombin-generating capacity within the vascular wall because SMC phenotypic modulation is a hallmark of hypertension. Materials and MethodsMaterials and Methods are available in the online-only Data Supplement. Results Hypertension-Associated Changes in Circulating Endothelial MarkersThe weight of SHR rats was significantly lower compared with the age-matched Wistar rats (94±5 versus 141±2 g at 5 weeks of age and 335±5...

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“…The role of the integrins in arterial stiffness is also supported by in vitro manipulations of smooth muscle cells showing that cyclic mechanical stress plays a role in the expression of integrins [ 63 ].…”

Section: Role Of Adhesion Structuresmentioning

confidence: 87%

Animal Models for Studies of Arterial Stiffness

Lacolley¹,

Thornton²,

Bézie³

2014

Blood Pressure and Arterial Wall Mechanics in Cardiovascular Diseases

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Arterial stiffness is a perfect example of translational research spanning the understanding of the molecular determinants of the arterial wall constituents and their organization to the physiology of normal and early vascular ageing.The most widely used parameter to investigate arterial stiffness in rodents is pulse wave velocity (PWV). The relation between strain and stress is also established to characterize the intrinsic behaviour of the arterial wall independent of geometric factors.The fi rst attempts to explain arterial stiffness by the properties of the structural components of the arterial wall addressed the role of the principal constituents, elastin and collagen fi bres and smooth muscle cells. To complete this approach, the roles of the adhesion molecules, infl ammation, blood pressure variability, NO, integrins and metalloproteinases in arterial stiffness were also investigated by attempting to try and interfere directly with these different factors.Hypertensive rodents were the fi rst experimental models used and employed to test remodelling and vascular function in an environment mimicking human physiology. Then, investigations were completed with other cardiovascular animal models (mainly kidney disease, obesity, blood pressure variability or ageing) to discover more specifi c therapeutic targets related to other mechanisms that trigger arterial stiffness. Nowadays, the advances in mouse genetics have provided numerous genotypes and phenotypes to study changes in arterial mechanics with disease progression and treatment. The aim of modifying a single gene to understand the Y. Bezie , PharmD, PhD Pharmacy Department , Groupe Hospitalier Paris Saint -Joseph , 185 re Raymond Losserand ,

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Cyclic stretch-induced thrombin generation by rat vascular smooth muscle cells is mediated by the integrin αvβ3 pathway

Abstract: These data show that the contribution of cyclic stretch to VSMC-supported thrombin generation is driven by the integrin α(v)β(3) signalling pathway and suggest a role for pulsatility-induced intramural thrombin in VSMC-dependent vascular remodelling.

Cited by 27 publications

References 33 publications

Mechanical Stretch Suppresses microRNA-145 Expression by Activating Extracellular Signal-Regulated Kinase 1/2 and Upregulating Angiotensin-Converting Enzyme to Alter Vascular Smooth Muscle Cell Phenotype

Mechanical Stretch Suppresses microRNA-145 Expression by Activating Extracellular Signal-Regulated Kinase 1/2 and Upregulating Angiotensin-Converting Enzyme to Alter Vascular Smooth Muscle Cell Phenotype

Vascular Smooth Muscle Cells Are Responsible for a Prothrombotic Phenotype of Spontaneously Hypertensive Rat Arteries

Animal Models for Studies of Arterial Stiffness

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