Angiotensin II–Mediated Microvascular Thrombosis

Senchenkova, Elena Y.; Russell, Janice; Almeida-Paula, Lidiana D.; Harding, Joseph W.; Granger, D. Neil

doi:10.1161/hypertensionaha.110.158220

Cited by 93 publications

(125 citation statements)

References 41 publications

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“…Reviewed in Garg et al (2012). Actions in the clotting system Platelet aggregation Platelet Increases platelet aggregation by a mechanism that involves AT1 receptor, AT2 receptor, and AT4 receptor (Senchenkova et al, 2010). Stimulates platelet activating factor synthesis (Neuwirth et al, 1989).…”

Section: Small and Large Intestinementioning

confidence: 99%

A Modern Understanding of the Traditional and Nontraditional Biological Functions of Angiotensin-Converting Enzyme

et al. 2012

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Section: Small and Large Intestinementioning

confidence: 99%

A Modern Understanding of the Traditional and Nontraditional Biological Functions of Angiotensin-Converting Enzyme

et al. 2012

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“…The concentration for half-maximum velocity (EC 50 ) for aggregation velocity of WT platelets in response to either thrombin or ADP was determined as described previously. 29 This method yielded an EC 50 of 0.63 U/mL for thrombin and 733nM for ADP. The EC 50 values were used to determine whether platelet aggregation velocity differed between control (WT3WT) and ␤ s 3WT mice.…”

Section: Platelet Aggregationmentioning

confidence: 97%

“…ANS was administered (75 g/mouse) IP 24 hours before the experiment. 29,30 A reduction in circulating neutrophils (1% Ϯ 5% in WT3WT and 88% Ϯ 6% in ␤ s 3WT) was verified by counting neutrophils in the peripheral blood before ANS injection and immediately before the experiment. ANS did not alter the number of circulating lymphocytes, monocytes, or platelets.…”

mentioning

confidence: 99%

Mechanisms of enhanced thrombus formation in cerebral microvessels of mice expressing hemoglobin-S

Gavins

Russell

Senchenkova

et al. 2011

Blood

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The microvasculature assumes an inflammatory and procoagulant state in a variety of different diseases, including sickle cell disease (SCD), which may contribute to the high incidence of ischemic stroke in these patients. This study provides evidence for accelerated thrombus formation in arterioles and venules in the cerebral vasculature of mice that express hemoglobin-S (␤ s mice). Enhanced microvascular thrombosis in ␤ s mice was blunted by immunologic or genetic interventions that target tissue factor, endothelial protein C receptor, activated protein C, or thrombin. Platelets from ␤ s mice also exhibited enhanced aggregation velocity after stimulation with thrombin but not ADP. Neutropenia also protected against the enhanced thrombosis response in ␤ s mice. These results indicate that the cerebral microvasculature is rendered vulnerable to thrombus formation in ␤ s mice via a neutrophil-dependent mechanism that is associated with an increased formation of and enhanced platelet sensitivity to thrombin. (Blood. 2011;117(15):4125-4133) IntroductionSickle cell disease (SCD) is a chronic, genetic disease affecting the vasculature of various organs, including the lungs and brain, with affected tissues assuming an inflammatory phenotype. 1 Sickle cell anemia is characterized by recurring acute vasoocclusive episodes and chronic damage to multiple organs. 2 Many morbid consequences of SCD, such as stroke (the prevalence of stroke in SCD patients is 8%-10%), are believed to result from microvascular blood flow impairment. 3,4 Histopathologic evaluation indicates that large vessel narrowing with superimposed thrombosis is the most common cause of ischemic stroke in children with SCD. 5 Risk factors for ischemic stroke in SCD patients include: a hemoglobin-S (HbS) phenotype, low steady-state Hb concentrations, high leukocyte counts, and elevated systolic blood pressure. 6 A fine balance normally exists between the procoagulant and anticoagulant functions of blood, allowing vessel walls to prevent unwanted hemorrhage and thrombosis. 3 SCD is associated with abnormalities in coagulant/anticoagulant pathways that tend to favor thrombus formation; these include: increased tissue factor (TF), accelerated thrombin generation, increased D-dimer (a marker of increased fibrolysis) and prothrombin fragment 1.2 (a marker of thrombin generation), and increased circulating fibrinogen, VWF, and clotting factors Patients with SCD also have reduced protein C and S levels. 10 Despite the large body of evidence supporting a hypercoagulable and prothrombotic state in SCD, it remains unclear whether increased thrombin and fibrin generation and platelet activation are primary or secondary events in this disease. 11 Furthermore, the few clinical studies on the use of antiplatelet agents (eg, aspirin and ticlopidine) and anticoagulant agents (eg, heparin and warfarin) in SCD patients have not provided convincing evidence to support this therapeutic strategy for the prevention or treatment of vasoocclusive complications. 11 Whereas mechanism...

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“…In vitro studies confirmed that Ang II induces the expression of TF in rat aortic endothelial cells [76] and human monocytes [77]. Chronic Ang II infusion induces platelet-endothelial cell adhesion [78] and accelerates thrombus formation in both large arteries [71,79] and arterioles [74]. TF in atherosclerotic plaques initiates blood coagulation, directly stimulates SMC proliferation and activates MMPs capable of degrading collagen.…”

Section: Role Of Ras In Atherosclerosis Progression and Acute Complicmentioning

confidence: 76%

“…The role of Ang II, as a mediator of thrombogenesis has been also supported by animal studies [71,72]. Namely, models of elevated Ang II levels, elicited both genetically and via chronic Ang II infusion, have demonstrated increased tissue factor (TF) expression and increased plasma plasminogen activator inhibitor-1 (PAI-1) level [73][74][75]. In vitro studies confirmed that Ang II induces the expression of TF in rat aortic endothelial cells [76] and human monocytes [77].…”

Section: Role Of Ras In Atherosclerosis Progression and Acute Complicmentioning

confidence: 99%

Involvement of the Renin‐Angiotensin System in Atherosclerosis

Kolaković¹,

Živković²,

Stanković³

2017

Renin-Angiotensin System - Past, Present and Future

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The renin-angiotensin system (RAS) is a well known for its role in the regulation of the blood pressure (BP). Angiotensin II (Ang II), the main mediator of the RAS, may act either, as a systemic molecule or a locally produced factor. Within the vessel wall it has significant proinflammatory role by inducing the oxidative stress, secretion of inflammatory cytokines and adhesion molecules. Ang II could trigger proliferation of vascular smooth muscle cells (VSMC) and its migration to the outer layer of the vessel wall. It could induce the release of matrix metalloproteinase (MMPs), from human VSMC and thus increase susceptibility to rupture of atherosclerotic lesions. Binding of Ang II to AT1R/AT2R could have opposing actions in vascular injury. The ACE2/Ang (1-7)/Mas axis of the RAS also opposes the unfavourable actions of ACE/Ang II/ATR1 axis. Inhibition of RAS could reduce inflammation-associated processes in vasculature, independently of lowering BP. RAS is significantly modulated by the genes coding for this system. Certain genetic variants (SNPs) in the RAS genes have been denoted as the functional ones and have been associated with hypertension, cardiovascular phenotypes and atherosclerosis. Also, the genetic components of the RAS interfere with the regulators of gene expression by microRNAs (miRs).

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Angiotensin II–Mediated Microvascular Thrombosis

Cited by 93 publications

References 41 publications

A Modern Understanding of the Traditional and Nontraditional Biological Functions of Angiotensin-Converting Enzyme

A Modern Understanding of the Traditional and Nontraditional Biological Functions of Angiotensin-Converting Enzyme

Mechanisms of enhanced thrombus formation in cerebral microvessels of mice expressing hemoglobin-S

Involvement of the Renin‐Angiotensin System in Atherosclerosis

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