Subscribe to RSS
DOI: 10.1055/s-0038-1676638
Disturbed Laminar Blood Flow Causes Impaired Fibrinolysis and Endothelial Fibrin Deposition In Vivo
Funding This study was funded by the Swedish Research Council VR 2015–02517, Swedish Society of Medicine SLS-500111, Swedish Research Council 522–2010–2823, Sahlgrenska University Hospital ALF research grant ALFGBG 622301, Stiftelsen Sigurd och Elsa Goljes Minne LA2017–0197 and Sahlgrenska University Hospital Research Grants 90170–8181.Publication History
03 May 2018
04 November 2018
Publication Date:
02 January 2019 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/201902/lookinside/thumbnails/10-1055-s-0038-1676638_180318-1.jpg)
Abstract
Endothelial expression of tissue-type plasminogen activator (t-PA) is crucial for maintaining an adequate endogenous fibrinolysis. It is unknown how endothelial t-PA expression and fibrinolysis are affected by blood flow in vivo. In this study, we investigated the impact of different blood flow profiles on endothelial t-PA expression and fibrinolysis in the arterial vasculature. Induction of disturbed laminar blood flow (D-flow) in the mouse carotid artery potently reduced endothelial t-PA messenger ribonucleic acid and protein expression, and caused fibrin deposition. En face immunohistochemistry demonstrated that arterial areas naturally exposed to D-flow had markedly lower endothelial t-PA levels than areas with sustained laminar blood flow (S-flow), and displayed pronounced fibrin deposition despite an intact endothelium. In t-PA and plasminogen-deficient mice, fibrin deposition did not extend into S-flow areas, indicating that areas of D-flow and S-flow differ, not only in fibrinolytic capacity, but also in coagulation. Furthermore, plasminogen accumulation was found at D-flow areas, and infusion of recombinant t-PA activated fibrinolysis and significantly reduced the fibrin deposits. In conclusion, D-flow potently impairs the fibrinolytic capacity and causes endothelial fibrin deposition in vivo. Our data also indicate that t-PA is the limiting factor for efficient fibrinolysis at the thrombosis-prone D-flow areas in the arterial vasculature.
* Per Fogelstrand and Niklas Bergh are senior co-authors of the study.
-
References
- 1 van Hinsbergh VW. Endothelium--role in regulation of coagulation and inflammation. Semin Immunopathol 2012; 34 (01) 93-106
- 2 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 (01) 117-122
- 3 Hrafnkelsdottir T, Gudnason T, Wall U, Jern C, Jern S. Regulation of local availability of active tissue-type plasminogen activator in vivo in man. J Thromb Haemost 2004; 2 (11) 1960-1968
- 4 Cesarman-Maus G, Hajjar KA. Molecular mechanisms of fibrinolysis. Br J Haematol 2005; 129 (03) 307-321
- 5 Davies PF. Hemodynamic shear stress and the endothelium in cardiovascular pathophysiology. Nat Clin Pract Cardiovasc Med 2009; 6 (01) 16-26
- 6 Dekker RJ, van Soest S, Fontijn RD. , et al. Prolonged fluid shear stress induces a distinct set of endothelial cell genes, most specifically lung Krüppel-like factor (KLF2). Blood 2002; 100 (05) 1689-1698
- 7 Chiu JJ, Chien S. Effects of disturbed flow on vascular endothelium: pathophysiological basis and clinical perspectives. Physiol Rev 2011; 91 (01) 327-387
- 8 Suo J, Ferrara DE, Sorescu D, Guldberg RE, Taylor WR, Giddens DP. Hemodynamic shear stresses in mouse aortas: implications for atherogenesis. Arterioscler Thromb Vasc Biol 2007; 27 (02) 346-351
- 9 Chatzizisis YS, Coskun AU, Jonas M, Edelman ER, Feldman CL, Stone PH. Role of endothelial shear stress in the natural history of coronary atherosclerosis and vascular remodeling: molecular, cellular, and vascular behavior. J Am Coll Cardiol 2007; 49 (25) 2379-2393
- 10 Malek AM, Alper SL, Izumo S. Hemodynamic shear stress and its role in atherosclerosis. JAMA 1999; 282 (21) 2035-2042
- 11 Gimbrone Jr MA, García-Cardeña G. Vascular endothelium, hemodynamics, and the pathobiology of atherosclerosis. Cardiovasc Pathol 2013; 22 (01) 9-15
- 12 Takada Y, Shinkai F, Kondo S. , et al. Fluid shear stress increases the expression of thrombomodulin by cultured human endothelial cells. Biochem Biophys Res Commun 1994; 205 (02) 1345-1352
- 13 Ankeny RF, Hinds MT, Nerem RM. Dynamic shear stress regulation of inflammatory and thrombotic pathways in baboon endothelial outgrowth cells. Tissue Eng Part A 2013; 19 (13-14): 1573-1582
- 14 Westmuckett AD, Lupu C, Roquefeuil S, Krausz T, Kakkar VV, Lupu F. Fluid flow induces upregulation of synthesis and release of tissue factor pathway inhibitor in vitro. Arterioscler Thromb Vasc Biol 2000; 20 (11) 2474-2482
- 15 Rana K, Neeves KB. Blood flow and mass transfer regulation of coagulation. Blood Rev 2016; 30 (05) 357-368
- 16 Neeves KB, Illing DA, Diamond SL. Thrombin flux and wall shear rate regulate fibrin fiber deposition state during polymerization under flow. Biophys J 2010; 98 (07) 1344-1352
- 17 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 (02) 291-298
- 18 Diamond SL, Sharefkin JB, Dieffenbach C, Frasier-Scott K, McIntire LV, Eskin SG. Tissue plasminogen activator messenger RNA levels increase in cultured human endothelial cells exposed to laminar shear stress. J Cell Physiol 1990; 143 (02) 364-371
- 19 Helenius G, Hagvall SH, Esguerra M, Fink H, Soderberg R, Risberg B. Effect of shear stress on the expression of coagulation and fibrinolytic factors in both smooth muscle and endothelial cells in a co-culture model. Eur Surg Res 2008; 40 (04) 325-332
- 20 Bergh N, Larsson P, Ulfhammer E, Jern S. Effect of shear stress, statins and TNF-α on hemostatic genes in human endothelial cells. Biochem Biophys Res Commun 2012; 420 (01) 166-171
- 21 Ulfhammer E, Carlström M, Bergh N, Larsson P, Karlsson L, Jern S. Suppression of endothelial t-PA expression by prolonged high laminar shear stress. Biochem Biophys Res Commun 2009; 379 (02) 532-536
- 22 Metallo CM, Vodyanik MA, de Pablo JJ, Slukvin II, Palecek SP. The response of human embryonic stem cell-derived endothelial cells to shear stress. Biotechnol Bioeng 2008; 100 (04) 830-837
- 23 Ny A, Leonardsson G, Hägglund AC. , et al. Ovulation in plasminogen-deficient mice. Endocrinology 1999; 140 (11) 5030-5035
- 24 Nam D, Ni CW, Rezvan A. , et al. Partial carotid ligation is a model of acutely induced disturbed flow, leading to rapid endothelial dysfunction and atherosclerosis. Am J Physiol Heart Circ Physiol 2009; 297 (04) H1535-H1543
- 25 Wang N, Miao H, Li YS. , et al. Shear stress regulation of Krüppel-like factor 2 expression is flow pattern-specific. Biochem Biophys Res Commun 2006; 341 (04) 1244-1251
- 26 Chappell DC, Varner SE, Nerem RM, Medford RM, Alexander RW. Oscillatory shear stress stimulates adhesion molecule expression in cultured human endothelium. Circ Res 1998; 82 (05) 532-539
- 27 Yrlid U, Holm M, Levin M. , et al. Endothelial repair is dependent on CD11c+ leukocytes to establish regrowing endothelial sheets with high cellular density. J Leukoc Biol 2018. Doi: 10.1002/JLB.4A1017-402RR
- 28 Kijani S, Yrlid U, Heyden M, Levin M, Borén J, Fogelstrand P. Filter-dense multicolor microscopy. PLoS One 2015; 10 (03) e0119499
- 29 De Wilde D, Trachet B, Debusschere N. , et al. Assessment of shear stress related parameters in the carotid bifurcation using mouse-specific FSI simulations. J Biomech 2016; 49 (11) 2135-2142
- 30 Balaguru UM, Sundaresan L, Manivannan J. , et al. Disturbed flow mediated modulation of shear forces on endothelial plane: a proposed model for studying endothelium around atherosclerotic plaques. Sci Rep 2016; 6: 27304
- 31 Larsson P, Alwis I, Niego B. , et al. Valproic acid selectively increases vascular endothelial tissue-type plasminogen activator production and reduces thrombus formation in the mouse. J Thromb Haemost 2016; 14 (12) 2496-2508
- 32 Zarins CK, Giddens DP, Bharadvaj BK, Sottiurai VS, Mabon RF, Glagov S. Carotid bifurcation atherosclerosis. Quantitative correlation of plaque localization with flow velocity profiles and wall shear stress. Circ Res 1983; 53 (04) 502-514
- 33 Vincenza Carriero M, Franco P, Vocca I. , et al. Structure, function and antagonists of urokinase-type plasminogen activator. Front Biosci 2009; 14: 3782-3794
- 34 Magnusson M, Larsson P, Lu EX, Bergh N, Carén H, Jern S. Rapid and specific hypomethylation of enhancers in endothelial cells during adaptation to cell culturing. Epigenetics 2016; 11 (08) 614-624
- 35 Shima DT, Saunders KB, Gougos A, D'Amore PA. Alterations in gene expression associated with changes in the state of endothelial differentiation. Differentiation 1995; 58 (03) 217-226
- 36 Uhlig S, Yang Y, Waade J, Wittenberg C, Babendreyer A, Kuebler WM. Differential regulation of lung endothelial permeability in vitro and in situ. Cell Physiol Biochem 2014; 34 (01) 1-19
- 37 Diamond SL, Eskin SG, McIntire LV. Fluid flow stimulates tissue plasminogen activator secretion by cultured human endothelial cells. Science 1989; 243 (4897): 1483-1485
- 38 Greve JM, Les AS, Tang BT. , et al. Allometric scaling of wall shear stress from mice to humans: quantification using cine phase-contrast MRI and computational fluid dynamics. Am J Physiol Heart Circ Physiol 2006; 291 (04) H1700-H1708
- 39 Sullivan CJ, Hoying JB. Flow-dependent remodeling in the carotid artery of fibroblast growth factor-2 knockout mice. Arterioscler Thromb Vasc Biol 2002; 22 (07) 1100-1105
- 40 Bergh N, Ulfhammer E, Glise K, Jern S, Karlsson L. Influence of TNF-alpha and biomechanical stress on endothelial anti- and prothrombotic genes. Biochem Biophys Res Commun 2009; 385 (03) 314-318
- 41 Bergh N, Ulfhammer E, Karlsson L, Jern S. Effects of two complex hemodynamic stimulation profiles on hemostatic genes in a vessel-like environment. Endothelium 2008; 15 (5-6): 231-238
- 42 Passerini AG, Milsted A, Rittgers SE. Shear stress magnitude and directionality modulate growth factor gene expression in preconditioned vascular endothelial cells. J Vasc Surg 2003; 37 (01) 182-190
- 43 Chiu JJ, Usami S, Chien S. Vascular endothelial responses to altered shear stress: pathologic implications for atherosclerosis. Ann Med 2009; 41 (01) 19-28
- 44 Ensley AE, Nerem RM, Anderson DE, Hanson SR, Hinds MT. Fluid shear stress alters the hemostatic properties of endothelial outgrowth cells. Tissue Eng Part A 2012; 18 (1-2): 127-136
- 45 Boon RA, Horrevoets AJ. Key transcriptional regulators of the vasoprotective effects of shear stress. Hamostaseologie 2009; 29 (01) 39-40
- 46 Lin Z, Kumar A, SenBanerjee S. , et al. Kruppel-like factor 2 (KLF2) regulates endothelial thrombotic function. Circ Res 2005; 96 (05) e48-e57
- 47 Reininger AJ, Heinzmann U, Reininger CB, Friedrich P, Wurzinger LJ. Flow mediated fibrin thrombus formation in an endothelium-lined model of arterial branching. Thromb Res 1994; 74 (06) 629-641
- 48 Lupu C, Westmuckett AD, Peer G. , et al. Tissue factor-dependent coagulation is preferentially up-regulated within arterial branching areas in a baboon model of Escherichia coli sepsis. Am J Pathol 2005; 167 (04) 1161-1172
- 49 Redlitz A, Tan AK, Eaton DL, Plow EF. Plasma carboxypeptidases as regulators of the plasminogen system. J Clin Invest 1995; 96 (05) 2534-2538