Impaired Endothelial Release of Tissue-Type Plasminogen Activator in Patients With Chronic Kidney Disease and Hypertension

Hrafnkelsdóttir, Thórdís; Ottosson, Pia; Guðnason, Þórarinn; Samuelsson, Ola; Jern, Sverker

doi:10.1161/01.hyp.0000137380.91476.fb

Cited by 54 publications

(33 citation statements)

References 35 publications

(25 reference statements)

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“…Measuring the capacity for tPA release may provide additional and novel insights into endothelial-like cell function. For example, it has been suggested that tPA release may be a more sensitive marker of endothelial dysfunction than previously thought, since it has been reported that patients with hypertension show normal endothelial-dependent vasodilation yet impaired tPA release [45]. HE-like cells cultured on POC secrete tPA in nonstimulated cultures and respond to thrombin stimulation by upregulating tPA secretion.…”

Section: Discussionmentioning

confidence: 99%

Toward Engineering a Human Neoendothelium with Circulating Progenitor Cells

et al. 2009

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Tissue-engineered vascular grafts may one day provide a solution to many of the limitations associated with using synthetic vascular grafts. However, identifying a suitable cell source and polymer scaffold to recreate the properties of a native blood vessel remains a challenge. In this work, we assess the feasibility of using endothelial progenitor cells (EPCs) found in circulating blood to generate a functional endothelium on poly(1,8-octanediol-co-citrate) (POC), a biodegradable elastomeric polyester. EPCs were isolated from human blood and biochemically differentiated into endothelial-like cells (HE-like) in vitro. The differentiated cell phenotype and function was confirmed by the appearance of the characteristic endothelial cell (EC) cobblestone morphology and positive staining for EC markers, von Willebrand factor, vascular endothelial cadherin, flk-1, and CD31. In addition, HE-like cells cultured on POC express endothelial nitric oxide synthase at levels comparable to aortic ECs. Furthermore, as with mature endothelial cells, HE-like cell populations show negligible expression of tissue factor. Similarly, HE-like cells produce and secrete prostacyclin and tissue plasminogen activator at levels comparable to venous and aortic ECs. When compared to fibroblast cells, HE-like cells cultured on POC show a decrease in the rate of plasma and wholeblood clot formation as well as a decrease in platelet adhesion. Finally, the data show that HE-like cells can withstand physiological shear stress of 10 dynes/cm 2 when cultured on POC-modified expanded poly(tetrafluoroethylene) vascular grafts. Collectively, these data are the foundation for future clinical studies in the creation of an autologous endothelial cell-seeded vascular graft. STEM CELLS 2010;28:318-328 Disclosure of potential conflicts of interest is found at the end of this article.

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Section: Discussionmentioning

confidence: 99%

Toward Engineering a Human Neoendothelium with Circulating Progenitor Cells

et al. 2009

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“…A reduced capacity to release t-PA has also been observed in subjects with an increased risk of myocardial infarction, i.e. smokers [7,8] and hypertensives [9,10]. It has, however, recently been shown, that the impairment in the latter group is reversible as it can be restored by anti-hypertensive therapy [11].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of carboxypeptidase U (TAFIa) activity improves rt-PA induced thrombolysis in a dog model of coronary artery thrombosis

Björkman

Abrahamsson

Nerme

et al. 2005

Thrombosis Research

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The physiologically most important activator of intravascular fibrinolysis is tissue-type plasminogen activator (t-PA) released from endothelial cells. In man, sympathomimetic drugs increase the systemic concentration of t-PA. It is therefore of interest to investigate whether cardiac sympathetic activation can induce a local t-PA release, which could counteract intra-coronary clot formation.Thrombolytic therapy with recombinant t-PA (rt-PA) is effective in acute myocardial infarction, but the treatment is limited by a fairly slow reperfusion rate and frequent early reocclusions. A potential mechanism behind early reocclusions might be that active thrombin is released from the thrombus during thrombolytic therapy. Thrombin has recently been shown to activate procarboxypeptidase U, which in its active form (CPU) down-regulates endogenous fibrinolysis. Therefore, one way of improving thrombolytic efficacy may be to combine rt-PA with a lowmolecular weight direct thrombin inhibitor, which theoretically could have a pro-fibrinolytic effect, either by inhibition of fibrin-bound thrombin and/or by inhibition of CPU activation. An alternative way may be direct inhibition of CPU.In a porcine model, experimental activation of cardiac sympathetic nerves by electrical stimulation at 1 and 8 Hz induced 5-and 20-fold increase in the release of both total and active t-PA together with frequency-dependent increases in heart rate, blood pressure, and coronary blood flow. The t-PA release was independent of the heart rate and coronary flow response, but local infusion of isoprenaline suggested that part of the t-PA response was mediated by stimulation of β-adrenergic receptors. Next, we studied the combined effect of rt-PA and thrombin inhibitors (melagatran, hirudin and heparin) in a canine model of copper coil-induced coronary thrombosis. The profibrinolytic effect of rt-PA, either measured as patency rate or time-to-patency, was significantly enhanced with the low-molecular weight direct thrombin inhibitor melagatran, but to a lesser degree by hirudin and heparin. In the same model it was shown that active CPU is produced locally in the coronary vascular bed during both thrombus formation and clot lysis. Inhibition of thrombin attenuated CPU formation and improved patency. A similar effect was obtained with a direct inhibitor of CPU.In conclusion, the coronary t-PA response to sympathetic stimulation may constitute a thromboprotective defence mechanism to counteract its prothrombotic effects on the systemic level. Furthermore, direct thrombin and/or CPU inhibition may be potential targets for prevention of thrombus formation via facilitation of the endogenous fibrinolytic system.

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“…In addition, patients with reduced renal function are more likely to develop pulmonary thromboembolism than those with normal kidney function [7]. Possible mechanisms for the phenomenon include enhanced activation of factor XIIa, factor VIIa, and fibrinogen, as well as inhibition of von Willebrand factor and tissue plasminogen activator in the patients with reduced renal function [8,9]. There is also a report of a rare case of ADPKD patient in which a thrombus formation was observed in the inferior vena cava (IVC) due to the compression of IVC by huge renal cysts [10].…”

Section: Discussionmentioning

confidence: 99%