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The flow dependency of Tie2 expression in endotoxemia

Neng F. Kurniati| Rianne M. Jongman| Franziska vom Hagen| Katherine C. Spokes| Jill Moser| Erzsébet Ravasz Regan| Guido Krenning| Jan-Renier A. J. Moonen| Martin C. Harmsen| Michel M. R. F. Struys| Hans-Peter Hammes| Jan G. Zijlstra| William C. Aird| Peter Heeringa| Grietje Molema| Matijs van Meurs
Original
Volume 39, Issue 7 / July , 2013

Pages 1262 - 1271

Abstract

Rationale

Tie2 is predominantly expressed by endothelial cells and is involved in vascular integrity control during sepsis. Changes in Tie2 expression during sepsis development may contribute to microvascular dysfunction. Understanding the kinetics and molecular basis of these changes may assist in the development of therapeutic intervention to counteract microvascular dysfunction.

Objective

To investigate the molecular mechanisms underlying the changes in Tie2 expression upon lipopolysaccharide (LPS) challenge.

Methods and results

Studies were performed in LPS and pro-inflammatory cytokine challenged mice as well as in mice subjected to hemorrhagic shock, primary endothelial cells were used for in vitro experiments in static and flow conditions. Eight hours after LPS challenge, Tie2 mRNA loss was observed in all major organs, while loss of Tie2 protein was predominantly observed in lungs and kidneys, in the capillaries. A similar loss could be induced by secondary cytokines TNF-α and IL-1β. Ang2 protein administration did not affect Tie2 protein expression nor was Tie2 protein rescued in LPS-challenged Ang2-deficient mice, excluding a major role for Ang2 in Tie2 down regulation. In vitro, endothelial loss of Tie2 was observed upon lowering of shear stress, not upon LPS and TNF-α stimulation, suggesting that inflammation related haemodynamic changes play a major role in loss of Tie2 in vivo, as also hemorrhagic shock induced Tie2 mRNA loss. In vitro, this loss was partially counteracted by pre-incubation with a pharmacologically NF-кB inhibitor (BAY11-7082), an effect further substantiated in vivo by pre-treatment of mice with the NF-кB inhibitor prior to the inflammatory challenge.

Conclusions

Microvascular bed specific loss of Tie2 mRNA and protein in vivo upon LPS, TNFα, IL-1β challenge, as well as in response to hemorrhagic shock, is likely an indirect effect caused by a change in endothelial shear stress. This loss of Tie2 mRNA, but not Tie2 protein, induced by TNFα exposure was shown to be controlled by NF-кB signaling. Drugs aiming at restoring vascular integrity in sepsis could focus on preventing the Tie2 loss.

Keywords

References

  1. Doi K, Leelahavanichkul A, Yuen PS, Star RA (2009) Animal models of sepsis and sepsis-induced kidney injury. J Clin Invest 119(10):2868–2878
    • View reference on publisher's website
    • View reference on PubMed
  2. Dauphinee SM, Karsan A (2006) Lipopolysaccharide signaling in endothelial cells. Lab Invest 86(1):9–22
    • View reference on publisher's website
    • View reference on PubMed
  3. Kim DH, Jung YJ, Lee AS, Lee S, Kang KP, Lee TH et al (2009) COMP-Angiopoietin-1 decreases lipopolysaccharide-induced acute kidney injury. Kidney Int 76:1180–1191
    • View reference on publisher's website
    • View reference on PubMed
  4. Liu SF, Ye X, Malik AB (1997) In vivo inhibition of nuclear factor-kappa B activation prevents inducible nitric oxide synthase expression and systemic hypotension in a rat model of septic shock. J Immunol 159(8):3976–3983
    • View reference on PubMed
  5. Pries AR, Secomb TW, Gaehtgens P (1995) Design principles of vascular beds. Circ Res 77(5):1017–1023
    • View reference on publisher's website
    • View reference on PubMed
  6. Nayak L, Lin Z, Jain MK (2011) “Go with the flow”: how Kruppel-like factor 2 regulates the vasoprotective effects of shear stress. Antioxid Redox Signal 15(5):1449–1461
    • View reference on publisher's website
    • View reference on PubMed
  7. van Meurs M, Kumpers P, Ligtenberg JJ, Meertens JH, Molema G, Zijlstra JG (2009) Bench-to-bedside review: angiopoietin signalling in critical illness—a future target? Crit Care 13(2):207
    • View reference on publisher's website
    • View reference on PubMed
  8. Wong AL, Haroon ZA, Werner S, Dewhirst MW, Greenberg CS, Peters KG (1997) Tie2 expression and phosphorylation in angiogenic and quiescent adult tissues. Circ Res 81(4):567–574
    • View reference on publisher's website
    • View reference on PubMed
  9. van Meurs M, Kurniati NF, Wulfert FM, Asgeirsdottir SA, de Graaf I, Satchell SC et al (2009) Shock-induced stress induces loss of microvascular endothelial Tie2 in the kidney which is not associated with reduced glomerular barrier function. Am J Physiol Renal Physiol 297(2):F272–F281
    • View reference on publisher's website
    • View reference on PubMed
  10. Hegeman MA, Hennus MP, van Meurs M, Cobelens PM, Kavelaars A, Jansen NJ et al (2010) Angiopoietin-1 treatment reduces inflammation but does not prevent ventilator-induced lung injury. PLoS ONE 5(12):e15653
    • View reference on publisher's website
    • View reference on PubMed
  11. David S, Ghosh CC, Kuempers P, Shushakova N, Van SP, Khankin EV et al (2011) Effects of a synthetic PEG-ylated Tie-2 agonist peptide on endotoxemic lung injury and mortality. Am J Physiol Lung Cell Mol Physiol 300:L851–L862
    • View reference on publisher's website
    • View reference on PubMed
  12. David S, Park JK, van Meurs M, Zijlstra JG, Koenecke C, Schrimpf C et al (2011) Acute administration of recombinant Angiopoietin-1 ameliorates multiple-organ dysfunction syndrome and improves survival in murine sepsis. Cytokine 55(2):251–259
    • View reference on publisher's website
    • View reference on PubMed
  13. Satchell SC, Tasman CH, Singh A, Ni L, Geelen J, von Ruhland CJ et al (2006) Conditionally immortalized human glomerular endothelial cells expressing fenestrations in response to VEGF. Kidney Int 69(9):1633–1640
    • View reference on publisher's website
    • View reference on PubMed
  14. Kuldo JM, Ogawara KI, Werner N, Asgeirsdottir SA, Kamps JA, Kok RJ et al (2005) Molecular pathways of endothelial cell activation for (targeted) pharmacological intervention of chronic inflammatory diseases. Curr Vasc Pharmacol 3(1):11–39
    • View reference on publisher's website
    • View reference on PubMed
  15. Jin E, Liu J, Suehiro J, Yuan L, Okada Y, Nikolova-Krstevski V et al (2009) Differential roles for ETS, CREB, and EGR binding sites in mediating VEGF receptor 1 expression in vivo. Blood 114(27):5557–5566
    • View reference on publisher's website
    • View reference on PubMed
  16. van Meurs M, Wulfert FM, Knol AJ, de Haes A, Houwertjes M, Aarts LP et al (2008) Early organ-specific endothelial activation during hemorrhagic shock and resuscitation. Shock 29(2):291–299
    • View reference on PubMed
  17. Atkins GB, Jain M (2007) Role of kruppel-like transcription factors in endothelial biology. Circ Res 100(12):1686–1695
    • View reference on publisher's website
    • View reference on PubMed
  18. Hay DC, Beers C, Cameron V, Thomson L, Flitney FW, Hay RT (2003) Activation of NF-kappaB nuclear transcription factor by flow in human endothelial cells. Biochim Biophys Acta 1642(1–2):33–44
    • View reference on publisher's website
    • View reference on PubMed
  19. Mohan S, Koyoma K, Thangasamy A, Nakano H, Glickman RD, Mohan N (2007) Low shear stress preferentially enhances IKK activity through selective sources of ROS for persistent activation of NF-kappaB in endothelial cells. Am J Physiol Cell Physiol 292(1):C362–C371
    • View reference on publisher's website
    • View reference on PubMed
  20. Wada Y, Otu H, Wu S, Abid MR, Okada H, Libermann T et al (2005) Preconditioning of primary human endothelial cells with inflammatory mediators alters the “set point” of the cell. FASEB J 19(13):1914–1916
    • View reference on PubMed
  21. De Backer D, Donadello K, Taccone FS, Ospina-Tascon G, Salgado D, Vincent JL (2011) Microcirculatory alterations: potential mechanisms and implications for therapy. Ann Intensive Care 1(1):27
    • View reference on publisher's website
    • View reference on PubMed
  22. Molema G, Aird WC (2012) Vascular heterogeneity in the kidney. Semin Nephrol 32(2):145–155
    • View reference on publisher's website
    • View reference on PubMed
  23. Bogdanovic E, Nguyen VP, Dumont DJ (2006) Activation of Tie2 by angiopoietin-1 and angiopoietin-2 results in their release and receptor internalization. J Cell Sci 119(Pt 17):3551–3560
    • View reference on publisher's website
    • View reference on PubMed
  24. Blackwell TS, Christman JW (1996) Sepsis and cytokines: current status. Br J Anaesth 77(1):110–117
    • View reference on publisher's website
    • View reference on PubMed
  25. Willam C, Koehne P, Jurgensen JS, Grafe M, Wagner KD, Bachmann S et al (2000) Tie2 receptor expression is stimulated by hypoxia and proinflammatory cytokines in human endothelial cells. Circ Res 87(5):370–377
    • View reference on publisher's website
    • View reference on PubMed
  26. Takagi H, Koyama S, Seike H, Oh H, Otani A, Matsumura M et al (2003) Potential role of the angiopoietin/tie2 system in ischemia-induced retinal neovascularization. Invest Ophthalmol Vis Sci 44(1):393–402
    • View reference on publisher's website
    • View reference on PubMed
  27. Park SW, Chen SW, Kim M, Brown KM, Kolls JK, D’Agati VD et al (2011) Cytokines induce small intestine and liver injury after renal ischemia or nephrectomy. Lab Invest 91(1):63–84
    • View reference on publisher's website
    • View reference on PubMed
  28. Gardiner SM, Kemp PA, March JE, Woolley J, Bennett T (1998) The influence of antibodies to TNF-alpha and IL-1beta on haemodynamic responses to the cytokines, and to lipopolysaccharide, in conscious rats. Br J Pharmacol 125(7):1543–1550
    • View reference on publisher's website
    • View reference on PubMed
  29. Morimatsu H, Ishikawa K, May CN, Bailey M, Bellomo R (2012) The systemic and regional hemodynamic effects of phenylephrine in sheep under normal conditions and during early hyperdynamic sepsis. Anesth Analg 115(2):330–342
    • View reference on publisher's website
    • View reference on PubMed
  30. Tran M, Tam D, Bardia A, Bhasin M, Rowe GC, Kher A et al (2011) PGC-1alpha promotes recovery after acute kidney injury during systemic inflammation in mice. J Clin Invest 121:4003–4014
    • View reference on publisher's website
    • View reference on PubMed
  31. Ellis CG, Bateman RM, Sharpe MD, Sibbald WJ, Gill R (2002) Effect of a maldistribution of microvascular blood flow on capillary O(2) extraction in sepsis. Am J Physiol Heart Circ Physiol 282(1):H156–H164
    • View reference on PubMed
  32. Ye X, Ding J, Zhou X, Chen G, Liu SF (2008) Divergent roles of endothelial NF-kappaB in multiple organ injury and bacterial clearance in mouse models of sepsis. J Exp Med 205(6):1303–1315
    • View reference on publisher's website
    • View reference on PubMed
  33. Adrian JE, Morselt HW, Suss R, Barnert S, Kok JW, Asgeirsdottir SA et al (2010) Targeted SAINT-O-Somes for improved intracellular delivery of siRNA and cytotoxic drugs into endothelial cells. J Control Release 144(3):341–349
    • View reference on publisher's website
    • View reference on PubMed

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