Regulation of Endothelial Activation and Vascular Inflammation by Shear Stress

  • Annapurna Nayak
  • Carola S. König
  • Uday Kishore
  • Paul C. EvansEmail author
Part of the Bioanalysis book series (BIOANALYSIS, volume 2)


Atherosclerosis is a multifactorial disorder caused by genetic and environmental factors such as cholesterol, obesity, hypertension, diabetes, and smoking and is the primary cause of morbidity and mortality worldwide. Blood flow is known to exert shear stress on the vascular endothelium. Atherosclerotic lesions occur predominantly at sites of low shear, whereas regions of the vasculature exposed to high shear are protected. Low shear stress leads to activation of endothelial cells which in turn can initiate inflammation. Shear stress can also modulate several signalling pathways mediated by the activated endothelial cells. The molecules involved in these signalling pathways can be atheroprotective or atherogenic. The aim of this chapter is to discuss the effects of low shear stress on the regulation of endothelial activation and subsequent vascular inflammation.


Shear Stress Human Umbilical Vein Endothelial Cell Endothelial Activation Laminar Shear Stress Oscillatory Shear Stress 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Mitogen activated protein kinase phosphatase 1


Kruppel like factor 2


Nuclear factor erythroid 2-related factor 2


Vascular cell adhesion molecule-1


Platelet-endothelial cell adhesion molecule-1


Intracellular cell adhesion molecule-1


Monocyte chemoattractant protein 1


c-Jun N-terminal kinase


Activating transcription factor 2


Nuclear factor κ-light-chain-enhancer of activated B cells


Nitric oxide


  1. 1.
    Abbas AB, Lichtman AH (2009) Basic immunology. Elsevier, Philadelphia, PAGoogle Scholar
  2. 2.
    Alon R, Kassner PD, Carr MW, Finger EB, Hemler ME, Springer TA (1995) The integrin VLA-4 supports tethering and rolling in flow on VCAM-1. J Cell Biol 128:1243–1253CrossRefGoogle Scholar
  3. 3.
    Andrews NC, Erdjument-Bromage H, Davidson MB, Tempst P, Orkin SH (1993) Erythroid transcription factor NF-E2 is a haematopoietic-specific basic-leucine zipper protein. Nature 362:722–728CrossRefGoogle Scholar
  4. 4.
    Campbell JJ, Qin S, Bacon KB, Mackay CR, Butcher EC (1996) Biology of chemokine and classical chemoattractant receptors: differential requirements for adhesion-triggering versus chemotactic responses in lymphoid cells. J Cell Biol 134:255–266CrossRefGoogle Scholar
  5. 5.
    Chandrasekharan UM, Yang L, Walters A, Howe P, DiCorleto PE (2004) Role of CL-100, a dual specificity phosphatase, in thrombin-induced endothelial cell activation. J Biol Chem 279:46678–46685CrossRefGoogle Scholar
  6. 6.
    Cheng C et al (2006) Atherosclerotic lesion size and vulnerability are determined by patterns of fluid shear stress. Circulation 113(23):2744–2753CrossRefGoogle Scholar
  7. 7.
    Chi HB et al (2006) Dynamic regulation of pro- and anti-inflammatory cytokines by MAPK phosphatase 1 (MKP-1) in innate immune responses. Proc Natl Acad Sci U S A 103:2274–2279CrossRefGoogle Scholar
  8. 8.
    Cuhlmann S et al (2011) Disturbed blood flow induces RelA expression via c-Jun N-terminal kinase 1: a novel mode of NF-κB regulation that promotes arterial inflammation. Circ Res 108:950–959CrossRefGoogle Scholar
  9. 9.
    Cunningham KS, Gotlieb AI (2005) The role of shear stress in the pathogenesis of atherosclerosis. Lab Invest 85(1):9–23Google Scholar
  10. 10.
    Dai G, Vaughn S, Zhang Y, Wang ET, Garcia-Cardena G, Gimbrone MA Jr (2007) Biomechanical forces in atherosclerosis-resistant vascular regions regulate endothelial redox balance via phosphoinositol 3-kinase/Akt-dependent activation of Nrf2. Circ Res 101:723–733CrossRefGoogle Scholar
  11. 11.
    Dekker RJ et al (2005) Endothelial KLF2 links local arterial shear stress levels to the expression of vascular tone-regulating genes. Am J Pathol 167:609–618CrossRefGoogle Scholar
  12. 12.
    Izumi Y et al (2001) Gene transfer of dominant-negative mutants of extracellular signal-regulated kinase and c-Jun NH2-terminal kinase prevents neointimal formation in balloon-injured rat artery. Circ Res 88:1120–1126CrossRefGoogle Scholar
  13. 13.
    Kamiya A, Bukhari R, Togawa T (1984) Adaptive regulation of wall shear stress optimizing vascular tree function. Bull Math Biol 46:127–137Google Scholar
  14. 14.
    Keyse SM, Emslie EA (1992) Oxidative stress and heat shock induce a human gene encoding a protein-tyrosine phosphatase. Nature 359:644–647CrossRefGoogle Scholar
  15. 15.
    Kinney CM, Chandrasekharan UM, Mavrakis L, DiCorleto PE (2008) VEGF and thrombin induce MKP-1 through distinct signaling pathways: role for MKP-1 in endothelial cell migration. Am J Physiol Cell Physiol 294:C241–C250CrossRefGoogle Scholar
  16. 16.
    Lai KH, Wang H, Lee WS, Jain MK, Lee ME, Haber E (1996) Mitogen-activated protein kinase phosphatase-1 in rat arterial smooth muscle cell proliferation. J Clin Invest 98:1560–1567CrossRefGoogle Scholar
  17. 17.
    Levesque MJ, Nerem RM (1985) The elongation and orientation of cultured endothelial cells in response to shear stress. J Biomech Eng 107:341–347CrossRefGoogle Scholar
  18. 18.
    Malek AM, Alper SL, Izumo S (1999) Hemodynamic shear stress and its role in atherosclerosis. JAMA 21(282):2035–2042CrossRefGoogle Scholar
  19. 19.
    Metzler B, Li CH, Hu YH, Sturm G, Ghaffari-Tabrizi N, Xu QB (1999) LDL stimulates mitogen-activated protein kinase phosphatase-1 expression, independent of LDL receptors, in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 19:1862–1871CrossRefGoogle Scholar
  20. 20.
    Osto E et al (2008) c-Jun N-terminal kinase 2 deficiency protects against hypercholesterolemia-induced endothelial dysfunction and oxidative stress. Circulation 118:2073–2080CrossRefGoogle Scholar
  21. 21.
    Parmar KM et al (2006) Integration of flow-dependent endothelial phenotypes by Kruppel-like factor 2. J Clin Invest 116:49–58CrossRefGoogle Scholar
  22. 22.
    Pedersen EM et al (1999) Distribution of early atherosclerotic lesions in the human abdominal aorta correlates with wall shear stresses measured in vivo. Eur J Vasc Endovasc Surg 18:328–333CrossRefGoogle Scholar
  23. 23.
    Plank MJ, Wall DJN, David T (2007) The role of endothelial calcium and nitric oxide in the localisation of atherosclerosis. Math Biosci 207:26–39MathSciNetzbMATHCrossRefGoogle Scholar
  24. 24.
    Pontrelli G et al (2011) Modelling wall shear stress in small arteries using the Lattice Boltzmann method: influence of the endothelial wall profile. Med Eng Phys 33:832–839CrossRefGoogle Scholar
  25. 25.
    Ross R (1999) Atherosclerosis—an inflammatory disease. N Engl J Med 340(2):115–126CrossRefGoogle Scholar
  26. 26.
    Shanmugavelayudam SK, Rubenstein DA, Yin W (2010) Effect of geometrical assumptions on numerical modeling of coronary blood flow under normal and disease conditions. J Biomech Eng 132:061004CrossRefGoogle Scholar
  27. 27.
    SenBanerjee S et al (2004) KLF2 Is a novel transcriptional regulator of endothelial proinflammatory activation. J Exp Med 199:1305–1315CrossRefGoogle Scholar
  28. 28.
    Stawowy P, Goetze S, Margeta C, Fleck E, Graf K (2003) LPS regulate ERK1/2-dependent signaling in cardiac fibroblasts via PKC-mediated MKP-1 induction. Biochem Biophys Res Commun 303:74–80CrossRefGoogle Scholar
  29. 29.
    Sun H, Charles CH, Lau LF, Tonks NF (1993) MKP-1 (3CH134), an immediate early gene product, is a dual specificity phosphatase that dephosphorylates MAP kinase in vivo. Cell 75:487–493CrossRefGoogle Scholar
  30. 30.
    Van der Heiden K, Cuhlmann S, Luong LA, Zakkar M, Evans PC (2010) Role of nuclear factor kappaB in cardiovascular health and disease. Clin Sci (Lond) 118:593–605CrossRefGoogle Scholar
  31. 31.
    Wadgaonkar R et al (2004) Regulation of c-Jun N-terminal kinase and p38 kinase pathways in endothelial cells. Am J Respir Cell Mol Biol 31:423–431CrossRefGoogle Scholar
  32. 32.
    Warabi E et al (2004) Effect on endothelial cell gene expression of shear stress, oxygen concentration, and low-density lipoprotein as studied by a novel flow cell culture system. Free Radic Biol Med 37:682–694CrossRefGoogle Scholar
  33. 33.
    Warabi E et al (2007) Shear stress stabilizes NF-E2-related factor 2 and induces antioxidant genes in endothelial cells: role of reactive oxygen/nitrogen species. Free Radic Biol Med 42:260–269CrossRefGoogle Scholar
  34. 34.
    Yin W, Shanmugavelayudam SK, Rubenstein DA (2009) 3D numerical simulation of coronary blood flow and its effect on endothelial cell activation. Conf Proc IEEE Eng Med Biol Soc 2009:4003–4006Google Scholar
  35. 35.
    Zakkar M et al (2009) Activation of Nrf2 in endothelial cells protects arteries from exhibiting a proinflammatory state. Arterioscler Thromb Vasc Biol 29:1851–1857CrossRefGoogle Scholar
  36. 36.
    Zakkar M et al (2008) Increased endothelial mitogen-activated protein kinase phosphatase-1 expression suppresses proinflammatory activation at sites that are resistant to atherosclerosis. Circ Res 103:726–732CrossRefGoogle Scholar
  37. 37.
    Zou YP, Qi Y, Roztocil E, Nicholl SM, Davies MG (2007) Patterns of kinase activation induced by injury in the murine femoral artery. J Surg Res 142:332–334CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Annapurna Nayak
    • 1
    • 2
  • Carola S. König
    • 3
  • Uday Kishore
    • 1
  • Paul C. Evans
    • 4
    Email author
  1. 1.Centre for Infection, Immunity and Disease Mechanisms, Biosciences, School of Health Sciences and Social CareBrunel UniversityLondonUK
  2. 2.Centre for Biotechnology and Bioinformatics, School of Life Sciences, Jawaharlal Nehru Institute for Advanced StudiesSecunderabadIndia
  3. 3.Brunel Institute for BioengineeringBrunel UniversityLondonUK
  4. 4.Department of Cardiovascular ScienceSheffield University Medical School, Sheffield UniversitySheffieldUK

Personalised recommendations