New insights into shear stress-induced endothelial signalling and barrier function: cell-free fluid versus blood flow

Xu, Shixin; Li, Xiang; LaPenna, Kyle B.; Yokota, Stanley D.; Huke, Sabine; He, Pingnian

doi:10.1093/cvr/cvx021

Cited by 22 publications

(21 citation statements)

References 46 publications

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“…Our results are in line with those from Takase et al [ 11 ] who perfused rat mesenteric arteries; there PDGF-BB stimulated NO-release even relaxed rat mesenteric arteries. The different characteristic of PDGF-BB-induced NO-release might be due to two facts; 1) Takase et al [ 11 ] exposed rat mesenteric arteries to shear stress, generally going ahead with endothelial NO-release [ 100 ], 2) systemic and pulmonary vessel behave different to similar stimuli [ 70 ].…”

Section: Discussionmentioning

confidence: 99%

PDGF-BB regulates the pulmonary vascular tone: impact of prostaglandins, calcium, MAPK- and PI3K/AKT/mTOR signalling and actin polymerisation in pulmonary veins of guinea pigs

et al. 2018

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BackgroundPlatelet-derived growth factor (PDGF)-BB and its receptor PDGFR are highly expressed in pulmonary hypertension (PH) and mediate proliferation. Recently, we showed that PDGF-BB contracts pulmonary veins (PVs) and that this contraction is prevented by inhibition of PDGFR-β (imatinib/SU6668). Here, we studied PDGF-BB-induced contraction and downstream-signalling in isolated perfused lungs (IPL) and precision-cut lung slices (PCLS) of guinea pigs (GPs).MethodsIn IPLs, PDGF-BB was perfused after or without pre-treatment with imatinib (perfused/nebulised), the effects on the pulmonary arterial pressure (PPA), the left atrial pressure (PLA) and the capillary pressure (Pcap) were studied and the precapillary (Rpre) and postcapillary resistance (Rpost) were calculated. Perfusate samples were analysed (ELISA) to detect the PDGF-BB-induced release of prostaglandin metabolites (TXA2/PGI2). In PCLS, the contractile effect of PDGF-BB was evaluated in pulmonary arteries (PAs) and PVs. In PVs, PDGF-BB-induced contraction was studied after inhibition of PDGFR-α/β, L-Type Ca2+-channels, ROCK/PKC, prostaglandin receptors, MAP2K, p38-MAPK, PI3K-α/γ, AKT/PKB, actin polymerisation, adenyl cyclase and NO. Changes of the vascular tone were measured by videomicroscopy. In PVs, intracellular cAMP was measured by ELISA.ResultsIn IPLs, PDGF-BB increased PPA, Pcap and Rpost. In contrast, PDGF-BB had no effect if lungs were pre-treated with imatinib (perfused/nebulised). In PCLS, PDGF-BB significantly contracted PVs/PAs which was blocked by the PDGFR-β antagonist SU6668. In PVs, inhibition of actin polymerisation and inhibition of L-Type Ca2+-channels reduced PDGF-BB-induced contraction, whereas inhibition of ROCK/PKC had no effect. Blocking of EP1/3- and TP-receptors or inhibition of MAP2K-, p38-MAPK-, PI3K-α/γ- and AKT/PKB-signalling prevented PDGF-BB-induced contraction, whereas inhibition of EP4 only slightly reduced it. Accordingly, PDGF-BB increased TXA2 in the perfusate, whereas PGI2 was increased in all groups after 120 min and inhibition of IP-receptors did not enhance PDGF-BB-induced contraction. Moreover, PDGF-BB increased cAMP in PVs and inhibition of adenyl cyclase enhanced PDGF-BB-induced contraction, whereas inhibition of NO-formation only slightly increased it.ConclusionsPDGF-BB/PDGFR regulates the pulmonary vascular tone by the generation of prostaglandins, the increase of calcium, the activation of MAPK- or PI3K/AKT/mTOR signalling and actin remodelling. More insights in PDGF-BB downstream-signalling may contribute to develop new therapeutics for PH.

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Section: Discussionmentioning

confidence: 99%

PDGF-BB regulates the pulmonary vascular tone: impact of prostaglandins, calcium, MAPK- and PI3K/AKT/mTOR signalling and actin polymerisation in pulmonary veins of guinea pigs

et al. 2018

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“…Thus, neutrophils and NETs are major contributors to atherothrombosis. Different from arteries, thrombosis in veins is usually initiated by endothelial injury (Di Nisio et al, 2016 ) triggered by alteration in the blood flow or endothelial dysfunction (Xu et al, 2017 ). Subsequently, damaged endothelial cells secrete massive amounts of von Willebrand factor and P-selectin, which adhere to platelets and recruit leukocytes (Etulain et al, 2015 ; Michels et al, 2016 ).…”

Section: Neutrophil Subpopulations In Diseasementioning

confidence: 99%

Neutrophil: A Cell with Many Roles in Inflammation or Several Cell Types?

2018

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Neutrophils are the most abundant leukocytes in the circulation, and have been regarded as first line of defense in the innate arm of the immune system. They capture and destroy invading microorganisms, through phagocytosis and intracellular degradation, release of granules, and formation of neutrophil extracellular traps after detecting pathogens. Neutrophils also participate as mediators of inflammation. The classical view for these leukocytes is that neutrophils constitute a homogenous population of terminally differentiated cells with a unique function. However, evidence accumulated in recent years, has revealed that neutrophils present a large phenotypic heterogeneity and functional versatility, which place neutrophils as important modulators of both inflammation and immune responses. Indeed, the roles played by neutrophils in homeostatic conditions as well as in pathological inflammation and immune processes are the focus of a renovated interest in neutrophil biology. In this review, I present the concept of neutrophil phenotypic and functional heterogeneity and describe several neutrophil subpopulations reported to date. I also discuss the role these subpopulations seem to play in homeostasis and disease.

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“…Moreover, shear-stress-induced EC released ATP alone was insufficient to increase [Ca 2+ ]i in ECs. While shear stress-induced endothelial NO production occurred in both cell free fluid and blood perfused vessels, shear stress-induced increases in EC cell [Ca 2+ ]i required the presence of RBCs, attributing to shearinduced pannexin-1 channel dependent release of ATP from RBCs [136]. The authors concluded that changes in blood flow alter vascular endothelial function through both wall shear stress and shear stress exerted on RBCs, and RBC released ATP plays an essential role in changes of EC signaling and vascular function.…”

Section: Role For Rbcs In Nitrite Homeostasis and Exercise Induced Camentioning

confidence: 98%

“…The resultant increase in vascular diameter, in its turn, would decrease the stimulus for deformation-induced ATP release and increase oxygen delivery to the tissue, resulting in improved matching of oxygen supply with metabolic demand [135]. Likewise, recent paper of Xu et al [136] highlighted the important role of RBC ATP release in the regulation of vascular tone in response to shear stress. They found that the levels of shear stress-induced release of ATP from RBCs at physiological hematocrits were about 3 orders of magnitude higher than those from ECs.…”

Section: Role For Rbcs In Nitrite Homeostasis and Exercise Induced Camentioning

confidence: 99%

Nanomedicine in Cancer Pathology

Rizzolio

2018

CMC

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Moderate exercise training is a key aspect of primary and secondary prevention strategies. Shear-induced upregulation of eNOS activity and function in the vascular endothelium is considered as one of the main molecular mechanisms of exercise-induced protection against myocardial ischemia/reperfusion (I/R) injury. It has been reported that levels of plasma nitrite, which are largely dependent on eNOS activity, were increased in healthy subjects after acute exercise, while this increase was abolished in coronary artery disease (CAD) patients. Our group and others demonstrated that RBCs contain a functional eNOS, which contributes to systemic nitrite homeostasis and to cardioprotection; moreover, expression and activity of red cell eNOS are decreased in CAD patients and significantly correlated with flow-mediated dilation, a diagnostic marker of endothelial function. Therefore, in addition to vascular eNOS, also red cell eNOS (or in more general terms NO metabolic activity of RBCs) may play a role in exercise-dependent changes of NO-bioavailability. In this review, we will focus on what is known and what is unknown about the role of RBCs in exercise-dependent cardioprotection with emphasis on RBC signaling and red cell eNOS. In detail, we will discuss the effects and molecular mechanisms of shear stress and exercise training on RBC signaling and function, review how these changes may influence blood rheology and systemic hemodynamics and highlight the potential role of red cell eNOS-mediated cardiovascular protection induced by physical activity against myocardial injury in animal and human studies and in clinical settings.

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New insights into shear stress-induced endothelial signalling and barrier function: cell-free fluid versus blood flow

Cited by 22 publications

References 46 publications

PDGF-BB regulates the pulmonary vascular tone: impact of prostaglandins, calcium, MAPK- and PI3K/AKT/mTOR signalling and actin polymerisation in pulmonary veins of guinea pigs

PDGF-BB regulates the pulmonary vascular tone: impact of prostaglandins, calcium, MAPK- and PI3K/AKT/mTOR signalling and actin polymerisation in pulmonary veins of guinea pigs

Neutrophil: A Cell with Many Roles in Inflammation or Several Cell Types?

Nanomedicine in Cancer Pathology

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