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Evidence for wall shear stress-dependent t-PA release in human conduit arteries: role of endothelial factors and impact of high blood pressure

Hypertension Research volume 44, pages 310–317 (2021)Cite this article

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.

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References

  1. Gorog DA. Prognostic value of plasma fibrinolysis activation markers in cardiovascular disease. J Am Coll Cardiol. 2010;55:2701–9.

    Article  CAS  Google Scholar 

  2. Muldowney JA, Vaughan DE. Tissue-type plasminogen activator release: new frontiers in endothelial function. J Am Coll Cardiol. 2002;40:967–9.

    Article  Google Scholar 

  3. Oliver JJ, Webb DJ, Newby DE. Stimulated tissue plasminogen activator release as a marker of endothelial function in humans. Arterioscler Thromb Vasc Biol. 2005;25:2470–9.

    Article  CAS  Google Scholar 

  4. Brown NJ. Blood pressure reduction and tissue-type plasminogen activator release. Hypertension. 2006;47:648–9.

    Article  CAS  Google Scholar 

  5. Emeis JJ. Regulation of the acute release of tissue-type plasminogen activator from the endothelium by coagulation activation products. Ann N Y Acad Sci. 1992;667:249–58.

    Article  CAS  Google Scholar 

  6. Diamond SL, Eskin SG, McIntire LV. Fluid flow stimulates tissue plasminogen activator secretion by cultured human endothelial cells. Science. 1989;243:1483–5.

    Article  CAS  Google Scholar 

  7. Kawai Y, Matsumoto Y, Watanabe K, Yamamoto H, Satoh K, Murata M, et al. Hemodynamic forces modulate the effects of cytokines on fibrinolytic activity of endothelial cells. Blood. 1996;87:2314–21.

    Article  CAS  Google Scholar 

  8. Sjögren LS, Gan L, Doroudi R, Jern C, Jungersten L, Jern S. Fluid shear stress increases the intra-cellular storage pool of tissue-type plasminogen activator in intact human conduit vessels. Thromb Haemost. 2000;84:291–8.

    Article  Google Scholar 

  9. Li N, Wallén NH, Hjemdahl P. Evidence for prothrombotic effects of exercise and limited protection by aspirin. Circulation. 1999;100:1374–9.

    Article  CAS  Google Scholar 

  10. Thrall G, Lane D, Carroll D, Lip GYH. A systematic review of the effects of acute psychological stress and physical activity on haemorheology, coagulation, fibrinolysis and platelet reactivity: Implications for the pathogenesis of acute coronary syndromes. Thromb Res. 2007;120:819–47.

    Article  CAS  Google Scholar 

  11. Gkaliagkousi E, Gavriilaki E, Douma S. Effects of acute and chronic exercise in patients with essential hypertension: benefits and risks. Am J Hypertens. 2015;28:429–39.

    Article  CAS  Google Scholar 

  12. Stein CM, Brown N, Vaughan DE, Lang CC, Wood AJ. Regulation of local tissue-type plasminogen activator release by endothelium-dependent and endothelium-independent agonists in human vasculature. J Am Coll Cardiol. 1998;32:117–22.

    Article  CAS  Google Scholar 

  13. Brown NJ, Gainer JV, Stein CM, Vaughan DE. Bradykinin stimulates tissue plasminogen activator release in human vasculature. Hypertension. 1999;33:1431–5.

    Article  CAS  Google Scholar 

  14. Hrafnkelsdóttir T, Wall U, Jern C, Jern S. Impaired capacity for endogenous fibrinolysis in essential hypertension. Lancet. 1998;352:1597–8.

    Article  Google Scholar 

  15. Giannarelli C, De Negri F, Virdis A, Ghiadoni L, Cipriano A, Magagna A, et al. Nitric oxide modulates tissue plasminogen activator release in normotensive subjects and hypertensive patients. Hypertension. 2007;49:878–84.

    Article  CAS  Google Scholar 

  16. Giannarelli C, Virdis A, De Negri F, Magagna A, Duranti E, Salvetti A, et al. Effect of sulfaphenazole on tissue plasminogen activator release in normotensive subjects and hypertensive patients. Circulation. 2009;119:1625–33.

    Article  CAS  Google Scholar 

  17. Robinson SD, Ludlam CA, Boon NA, Newby DE. Endothelial fibrinolytic capacity predicts future adverse cardiovascular events in patients with coronary heart disease. Arterioscler Thromb Vasc Biol. 2007;27:1651–6.

    Article  CAS  Google Scholar 

  18. Brown NJ, Gainer JV, Murphey LJ, Vaughan DE. Bradykinin stimulates tissue plasminogen activator release from human forearm vasculature through B(2) receptor-dependent, NO synthase-independent, and cyclooxygenase-independent pathway. Circulation. 2000;102:2190–6.

    Article  CAS  Google Scholar 

  19. Smith DT, Hoetzer GL, Greiner JJ, Stauffer BL, DeSouza CA. Endothelial release of tissue-type plasminogen activator in the human forearm: role of nitric oxide. J Cardiovasc Pharm. 2003;42:311–4.

    Article  CAS  Google Scholar 

  20. Pretorius M, Brown NJ. Endogenous nitric oxide contributes to bradykinin-stimulated glucose uptake but attenuates vascular tissue-type plasminogen activator release. J Pharm Exp Ther. 2010;332:291–7.

    Article  CAS  Google Scholar 

  21. Rahman AM, Murrow JR, Ozkor MA, Kavtaradze N, Lin J, De Staercke C, et al. Endothelium-derived hyperpolarizing factor mediates bradykinin-stimulated tissue plasminogen activator release in humans. J Vasc Res. 2014;51:200–8.

    Article  CAS  Google Scholar 

  22. Bellien J, Iacob M, Gutierrez L, Isabelle M, Lahary A, Thuillez C, et al. Crucial role of NO and endothelium-derived hyperpolarizing factor in human sustained conduit artery flow-mediated dilatation. Hypertension. 2006;48:1088–94.

    Article  CAS  Google Scholar 

  23. Bellien J, Iacob M, Remy-Jouet I, Lucas D, Monteil C, Gutierrez L, et al. Epoxyeicosatrienoic acids contribute with altered nitric oxide and endothelin-1 pathways to conduit artery endothelial dysfunction in essential hypertension. Circulation. 2012;125:1266–75.

    Article  CAS  Google Scholar 

  24. Lorthioir A, Joannidès R, Rémy-Jouet I, Fréguin-Bouilland C, Iacob M, Roche C, et al. Polycystin deficiency induces dopamine-reversible alterations in flow-mediated dilatation and vascular nitric oxide release in humans. Kidney Int. 2015;87:465–72.

    Article  CAS  Google Scholar 

  25. Eliasson M, Jansson JH, Nilsson P, Asplund K. Increased levels of tissue plasminogen activator antigen in essential hypertension. A population-based study in Sweden. J Hypertens. 1997;15:349–56.

    Article  CAS  Google Scholar 

  26. Poli KA, Tofler GH, Larson MG, Evans JC, Sutherland PA, Lipinska I, et al. Association of blood pressure with fibrinolytic potential in the Framingham offspring population. Circulation. 2000;101:264–9.

    Article  CAS  Google Scholar 

  27. Tarutani Y, Matsumoto T, Takashima H, Yamane T, Horie M. Brachial artery flow-mediated vasodilation is correlated with coronary vasomotor and fibrinolytic responses induced by bradykinin. Hypertens Res. 2005;28:59–66.

    Article  CAS  Google Scholar 

  28. Bellien J, Remy-Jouet I, Iacob M, Blot E, Mercier A, Lucas D D, et al. Impaired role of epoxyeicosatrienoic acids in the regulation of basal conduit artery diameter during essential hypertension. Hypertension. 2012;60:1415–21.

    Article  CAS  Google Scholar 

  29. Hrafnkelsdóttir T, Wall U, Jern C, Jern S. Impaired capacity for endogenous fibrinolysis in essential hypertension. Lancet. 1998;352:1597–8.

    Article  Google Scholar 

  30. Ridderstråle W, Ulfhammer E, Jern S, Hrafnkelsdóttir T. Impaired capacity for stimulated fibrinolysis in primary hypertension is restored by antihypertensive therapy. Hypertension. 2006;47:686–91.

    Article  Google Scholar 

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Acknowledgements

The authors thank Mrs Elizabeth Debray and Agnès Deshayes (Department of Hematology, Rouen University Hospital, France) for their technical help in the measurements of t-PA and PAP complex levels.

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Authors and Affiliations

  1. Department of Pharmacology, Rouen University Hospital, 76000, Rouen, France

    Jérémy Bellien, Michele Iacob, Vincent Richard, Julien Wils & Robinson Joannidès

  2. Normandie Univ, UNIROUEN, INSERM U1096, FHU REMOD-VHF, 76000, Rouen, France

    Jérémy Bellien, Michele Iacob, Vincent Richard, Julien Wils, Veronique Le Cam-Duchez & Robinson Joannidès

  3. Centre d’Investigation Clinique (CIC)-INSERM 1404, Rouen University Hospital, 76000, Rouen, France

    Jérémy Bellien & Robinson Joannidès

  4. Department of Hematology, Rouen University Hospital, 76000, Rouen, France

    Veronique Le Cam-Duchez

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Correspondence to Jérémy Bellien.

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Bellien, J., Iacob, M., Richard, V. et al. Evidence for wall shear stress-dependent t-PA release in human conduit arteries: role of endothelial factors and impact of high blood pressure. Hypertens Res 44, 310–317 (2021). https://doi.org/10.1038/s41440-020-00554-5

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