Hypertension Research https://doi.org/10.1038/s41440-020-00554-5 ARTICLE Evidence for wall shear stress-dependent t-PA release in human conduit arteries: role of endothelial factors and impact of high blood pressure Jérémy Bellien 1,2,3 ● Michele Iacob 1,2 ● Vincent Richard 1,2 ● Julien Wils 1,2 ● Veronique Le Cam-Duchez 2,4 ● Robinson Joannidès 1,2,3 Received: 3 July 2020 / Revised: 17 August 2020 / Accepted: 24 August 2020 © The Japanese Society of Hypertension 2020 Abstract Tissue plasminogen activator (t-PA) converts plasminogen into the serine protease plasmin, which in turn degrades fibrin clots. This study assessed whether an increase in shear stress is associated in humans in vivo with the release of t-PA in peripheral conduit arteries, the impact of high blood pressure and the role of NO and CYP450-derived epoxyeicosatrienoic acids (EETs). Local t-PA levels were quantified at baseline and during a sustained increase in radial artery wall shear stress induced by hand skin heating (from 34 to 44 °C) in a total of 25 subjects, among whom 8 were newly diagnosed essential hypertensive patients. The impact of the brachial infusion of NO synthase (L-NMMA) and CYP450 inhibitors (fluconazole) on t-PA release was assessed. The increase in shear stress induced by heating was associated with an increase in local t-PA release (from 3.0 ± 0.5 to 19.2 ± 5.5 ng/min, n = 25, P < 0.01). The magnitude of t-PA release was positively correlated with the increase in shear stress (r = 0.64, P < 0.001) and negatively correlated with mean blood pressure (r = -0.443, P = 0.027). These associations persisted after multiple adjustments for confounding factors. Finally, t-PA release was reduced by L-NMMA and to a larger extent by the combination of L-NMMA and fluconazole without a change in shear stress. The increase in wall shear stress in the peripheral conduit arteries induces a release of t-PA by a mechanism involving NO and EETs. The alteration of this response by high blood pressure may contribute to reducing the fibrinolytic potential and enhancing the risk of arterial thrombosis during exercise. Keywords Tissue-plasminogen activator ● Wall shear stress ● Conduit arteries ● Endothelium ● Hypertension Introduction Endogenous fibrinolysis is a protective mechanism against the formation of arterial thrombi and occlusion, which are the leading causes of myocardial infarction and stroke [1–4]. One pivotal enzyme of the fibrinolytic system is tissue plasminogen activator (t-PA), which converts plas- minogen into the serine protease plasmin, which, in turn, degrades fibrin clots [1–4]. In vitro experiments have demonstrated that t-PA is both constitutively secreted and can be released rapidly by endothelial cells, especially in response to coagulation activation products, such as thrombin [5], and to an increase in shear stress [6, 7]. However, ex vivo experiments have challenged this last result, showing that high shear stress applied in umbilical vein segments upregulates the intracellular storage pool of t- PA in the vascular wall but does not cause acute release [8]. In humans, the prothrombotic effects of physical exercise, * Jérémy Bellien jeremy.bellien@chu-rouen.fr 1 Department of Pharmacology, Rouen University Hospital, 76000 Rouen, France 2 Normandie Univ, UNIROUEN, INSERM U1096, FHU REMOD- VHF, 76000 Rouen, France 3 Centre d’Investigation Clinique (CIC)-INSERM 1404, Rouen University Hospital, 76000 Rouen, France 4 Department of Hematology, Rouen University Hospital, 76000 Rouen, France Supplementary information The online version of this article (https:// doi.org/10.1038/s41440-020-00554-5) contains supplementary material, which is available to authorized users. 1234567890();,: 1234567890();,: