Thrombin-Induced Responses via Protease-Activated Receptor 1 Blocked by the Endothelium on Isolated Porcine Retinal Arterioles

Takahashi, Kengo; Omae, Tsuneaki; Ono, Shinji; Kamiya, Tomoya; Tanner, Akira; Yoshida, Akitoshi

doi:10.1080/02713683.2018.1496266

Cited by 3 publications

(4 citation statements)

References 66 publications

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“… 97 These effects are heterogeneous but can be mediated by PAR1-dependent mechanisms. 98 Importantly, pro-remodelling effects of thrombin on VSMCs are mediated by NADPH oxidase (Nox) 2 and Nox5 generated reactive oxygen species (ROS). Nox5-dependent effects may be related to the fact that this oxidase is calcium dependent and thrombin, acting on PAR1, increases cytosolic Ca 2+ concentration in ECs.…”

Section: Coagulation and Ec Dysfunction: First Step In Atherogenesismentioning

confidence: 99%

Pleiotropic actions of factor Xa inhibition in cardiovascular prevention: mechanistic insights and implications for anti-thrombotic treatment

Cate

Guzik

Eikelboom

et al. 2020

Cardiovascular Research

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Atherosclerosis is a chronic inflammatory disease in which atherothrombotic complications lead to cardiovascular morbidity and mortality. At advanced stages, myocardial infarction, ischemic stroke and peripheral artery disease (PAD), including major adverse limb events (MALE), are caused either by acute occlusive atherothrombosis, or by thromboembolism. Endothelial dysfunction, vascular smooth muscle cell activation and vascular inflammation are essential in the development of acute cardiovascular events. Effects of the coagulation system on vascular biology extend beyond thrombosis. Under physiological conditions, coagulation proteases in blood are pivotal in maintaining hemostasis and vascular integrity. Under pathological conditions, including atherosclerosis, the same coagulation proteases (including factor Xa, factor VIIa and thrombin) become drivers of atherothrombosis, working in concert with platelets and vessel wall components. While initially atherothrombosis was attributed primarily to platelets, recent advances indicate the critical role of fibrin clot and plasma coagulation factors. Mechanisms of atherothrombosis and hypercoagulability vary depending on plaque erosion or plaque rupture. In addition to contributing to thrombus formation, factor Xa and thrombin can affect endothelial dysfunction, oxidative stress, vascular smooth muscle cell function as well as immune cell activation and vascular inflammation. By these mechanisms they promote atherosclerosis and contribute to plaque instability. In this review, we first discuss the postulated vasoprotective mechanisms of protease activated receptor (PARs) signaling induced by coagulation enzymes under physiological conditions. Next, we discuss preclinical studies linking coagulation with endothelial cell dysfunction, thromboinflammation and atherogenesis. Understanding these mechanisms is pivotal for the introduction of novel strategies in cardiovascular prevention and therapy. We therefore translate these findings to clinical studies of direct oral anticoagulant (DOAC) drugs and discuss the potential relevance of dual pathway inhibition for atherothrombosis prevention and vascular protection.

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Section: Coagulation and Ec Dysfunction: First Step In Atherogenesismentioning

confidence: 99%

Pleiotropic actions of factor Xa inhibition in cardiovascular prevention: mechanistic insights and implications for anti-thrombotic treatment

Cate

Guzik

Eikelboom

et al. 2020

Cardiovascular Research

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show abstract

“…Other studies have shown that thrombin causes vasoconstriction in cerebral arteries. 13,14 However, little is known about thrombin's vasoactive properties in cerebral vessels in rats, and its impacts during pregnancy and ePE. PARs 1 and 2 can mediate COX activation and NOS production.…”

Section: Discussionmentioning

confidence: 99%

“…3,12 Thrombin is a platelet-activated serine protease that drives the coagulation cascade by cleaving fibrinogen into fibrin, which cross-links to stabilize platelet plug formation and arrest bleeding. 12,13 Thrombin can also play a nonhemostatic role in arresting bleeding as a vasoactive circulatory protein. It has been shown to be a vasoconstrictor through protease-activated receptors (PARs) in the circulation of multiple organ systems, including cerebral arteries.…”

Section: Introductionmentioning

confidence: 99%

“…It has been shown to be a vasoconstrictor through protease-activated receptors (PARs) in the circulation of multiple organ systems, including cerebral arteries. 13,14 More recently, the use of selective PAR agonists has revealed that PAR regulation and vasoactivity vary with species and in tissues. 15 For example, in human omental arteries, PAR1 activation was shown to increase sensitivity to the vasoconstrictor effects of matrix metalloproteinase-1 but had no effect in rat basilar arteries.…”

Section: Introductionmentioning

confidence: 99%

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Thrombin in Pregnancy and Preeclampsia: Expression, Localization, and Vasoactivity in Brain and Microvessels From Rats

O'Brien,

Tremble,

Kropf

et al. 2024

Journal of Cardiovascular Pharmacology

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Thrombin is a coagulation factor increased in pregnancy and further increased in preeclampsia (PE), a hypertensive disorder. Thrombin is also expressed in brain and may have a nonhemostatic role. We characterized thrombin expression and vasoactivity in brain cerebral parenchymal arterioles (PAs) in rat models of pregnancy and PE. PAs were isolated and pressurized from nonpregnant (NP), late-pregnant (LP) rats and rats with experimental preeclampsia (ePE). Reactivity to thrombin (1-50 U/mL) was measured in the absence and presence of inhibition of cyclooxygenase (COX) and nitric oxide synthase (NOS). Plasma levels of prothrombin, thrombin-antithrombin (TAT), tissue plasminogen activator, and plasminogen activator inhibitor-1 (PAI-1) and cerebrospinal fluid (CSF) levels of TAT were compared via ELISA. Expression of protease-activated receptor (PAR) types 1 and 2 in PAs were measured by Western blot and immunohistochemistry. Neuronal thrombin expression was quantified in brains from all groups by immunohistochemistry. Prothrombin and TAT were elevated in ePE plasma compared to NP and LP. TAT was detected in CSF from all groups and significantly elevated in LP (NP: 0.137±0.014 ng/mL, LP: 0.241±0.015 ng/mL, ePE: 0.192±0.028 ng/mL; p<0.05). Thrombin caused modest vasoconstriction in PAs from all groups regardless of COX or NOS inhibition. PAR1 and PAR2 were found in PAs from all groups co-localized to smooth muscle. Thrombin expression in central neurons was decreased in both LP and ePE groups compared to NP. These findings suggest a role for thrombin and other hemostatic changes during pregnancy and PE beyond coagulation.

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Integrative phosphoproteomic analyses reveal hemostatic-endothelial signaling interplay

Groten,

van den Eshof,

van Alphen

et al. 2024

Journal of Thrombosis and Haemostasis

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Thrombin-Induced Responses via Protease-Activated Receptor 1 Blocked by the Endothelium on Isolated Porcine Retinal Arterioles

Cited by 3 publications

References 66 publications

Pleiotropic actions of factor Xa inhibition in cardiovascular prevention: mechanistic insights and implications for anti-thrombotic treatment

Pleiotropic actions of factor Xa inhibition in cardiovascular prevention: mechanistic insights and implications for anti-thrombotic treatment

Thrombin in Pregnancy and Preeclampsia: Expression, Localization, and Vasoactivity in Brain and Microvessels From Rats

Integrative phosphoproteomic analyses reveal hemostatic-endothelial signaling interplay

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