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Thromb Haemost 2013; 110(04): 785-794
DOI: 10.1160/TH13-01-0022
Endothelium and Vascular Development
Schattauer GmbH

Age-associated pro-inflammatory adaptations of the mouse thoracic aorta

Bianca Hemmeryckx
1   Center for Molecular and Vascular Biology, KU Leuven, Leuven, Belgium
,
Marc F. Hoylaerts
1   Center for Molecular and Vascular Biology, KU Leuven, Leuven, Belgium
,
Eveline Deloose
1   Center for Molecular and Vascular Biology, KU Leuven, Leuven, Belgium
3   Present address: Translational Research in Gastrointestinal Disorders, KU Leuven, Leuven, Belgium
,
Cor E. Van Hove
2   Division of Pharmacology, Universiteit Antwerpen, Wilrijk, Belgium
,
Paul Fransen
2   Division of Pharmacology, Universiteit Antwerpen, Wilrijk, Belgium
,
Hidde Bult
2   Division of Pharmacology, Universiteit Antwerpen, Wilrijk, Belgium
,
H. Roger Lijnen
1   Center for Molecular and Vascular Biology, KU Leuven, Leuven, Belgium
› Author Affiliations Financial Support: The Center for Molecular and Vascular Biology is supported by the “Programmafinanciering Katholieke Universiteit Leuven” (PF/10/014). This study was supported by FWO project G.0678.10.
Further Information

Publication History

Received: 10 January 2013

Accepted after major revision: 03 July 2013

Publication Date:
01 December 2017 (online)

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Summary

Arterial ageing may be associated with a reduction in vasodilation due to increased reactive oxygen species (ROS) production, whereas endothelial cell activation induces procoagulant changes. However, little is known on the effect of ageing on expression of anticoagulant endothelial markers such as endothelial protein C receptor (EPCR). To study age-associated alterations in smooth muscle cell (SMC) and endothelial cell (EC) structure and function, the aorta was isolated from 10-week-and 12– and 24-month-old C57BL/6J mice and analysed for its expression of genes involved in senescence, oxidative stress production, coagulation and matrix remodelling. In addition, vasorelaxation experiments were performed using 10-week-and 24-month-old thoracic aortic ring segments in organ chamber baths. The media thickness of the thoracic aorta progressively increased with age, associated with hypertrophy of vascular SMCs. Basal nitric oxide production and sensitivity to acetylcholine-mediated vasodilation in thoracic aorta rings was reduced with age, whereas no significant differences in ROS production could be demonstrated. Gene expression of tissue factor, EPCR and von Willebrand factor was not affected by ageing of the aorta, whereas that of thrombomodulin was mildly reduced and that of xanthine dehydrogenase, NADPH oxidase 4, tumour necrosis factor-α and vascular cell adhesion molecule-1 significantly enhanced. In conclusion, a reduction in endothelial cell-mediated vasodilation in aged thoracic aortas of C57BL/6J mice was accompanied by a shift towards a pro-inflammatory state of the endothelium.

Keywords

Vascular ageing - C57BL/6J mice - endothelial dysfunction - EPCR
 

  • References

  • 1 Wilkerson WR, Sane DC. Aging and thrombosis. Semin Thromb Hemost 2002; 28: 555-568.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 2 Makin A, Silverman SH, Lip GYH. Peripheral vascular disease and Virchow’s triad for thrombogenesis. Q J Med 2002; 95: 199-210.
    CrossrefPubMedGoogle Scholar
  • 3 van der Loo B, Labugger R, Skepper JN. et al. Enhanced peroxynitrite formation is associated with vascular aging. J Exp Med 2000; 192: 1731-1744.
    CrossrefPubMedGoogle Scholar
  • 4 Brandes RP, Fleming I, Russe R. Endothelial aging. Cardiovasc Res 2005; 66: 286-294.
    CrossrefPubMedGoogle Scholar
  • 5 Donato AJ, Eskurza I, Silver AE. et al. Direct evidence of endothelial oxidative stress with aging in humans in relation to impaired endothelium-dependent dilation and upregulation of nuclear factor-kappa B. Circulation Res 2007; 100: 1659-1666.
    CrossrefPubMedGoogle Scholar
  • 6 Kollander R, Solovey A, Milbauer LC. et al. Nuclear factor-kappa B (NFkappaB) component p50 in blood mononuclear cells regulates endothelial tissue factor expression in sickle transgenic mice: implications for the coagulopathy of sickle cell disease. Transl Res 2010; 155: 170-177.
    CrossrefPubMedGoogle Scholar
  • 7 Vaughan DE. PAI-1 and atherothrombosis. J Thromb Haemost 2005; 3: 1879-1883.
    CrossrefPubMedGoogle Scholar
  • 8 Reininger AJ. Function of von Willebrand factor in haemostasis and thrombosis. Haemophilia 2008; 14: 11-26.
    CrossrefPubMedGoogle Scholar
  • 9 Stämpfli SF, Akhmedov A, Gebhard C. et al. Aging induces endothelial dysfunction while sparing arterial thrombosis. Arterioscler Thromb Vasc Biol 2010; 30: 1960-1967.
    CrossrefPubMedGoogle Scholar
  • 10 Starr ME, Ueda J, Takahashi H. et al. Age-dependent vulnerability to endotoxemia is associated with reduction of anticoagulant factors activated protein C and thrombomodulin. Blood 2010; 115: 4886-4893.
    CrossrefPubMedGoogle Scholar
  • 11 Dahlback B, Villoutreix BO. The anticoagulant protein C pathway. FEBS Lett 2005; 579: 3310-3316.
    CrossrefPubMedGoogle Scholar
  • 12 Esmon CT. Protein C anticoagulant-anti-inflammatory effects. Semin Immunopathol 2012; 34: 127-132.
    CrossrefPubMedGoogle Scholar
  • 13 Chen XD, Tian L, Li M. et al. Relationship between endothelial cell protein C receptor gene 693A/G polymorphisms and deep venous thrombosis. Chin Med J (Engl) 2011; 124: 72-75.
    PubMedGoogle Scholar
  • 14 Van de Water NS, French JK, McDowell J. et al. The endothelial protein C receptor (EPCR) 23 bp insert in patients with myocardial infarction. Thromb Haemost 2001; 85: 749-751.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Wang J, Yang L, Rezaie AR. et al. Activated protein C protects against myocardial ischaemic/reperfusion injury through AMP-activated protein kinase signalling. J Thromb Haemost 2011; 9: 1308-1317.
    CrossrefPubMedGoogle Scholar
  • 16 Hemmeryckx B, Emmerechts J, Bovill EG. et al. Effect of ageing on the murine venous circulation. Histochem Cell Biol 2012; 137: 537-546.
    CrossrefPubMedGoogle Scholar
  • 17 Zhang J, Burridge KA, Friedman MH. In vivo differences between endothelial transcriptional profiles of coronary and iliac arteries revealed by microarray analysis. Am J Physiol Heart Circ Physiol 2008; 295: H1556-H1661.
    CrossrefPubMedGoogle Scholar
  • 18 Hemmeryckx B, Van Hove CE, Fransen P. et al. Progression of the prothrombotic state in ageing Bmal1-deficient mice. Arterioscler Thromb Vasc Biol 2011; 31: 2552-2559.
    CrossrefPubMedGoogle Scholar
  • 19 Fransen P, Van Assche T, Guns PJ. et al. Endothelial function in aorta segments of apolipoprotein E-deficient mice before development of atherosclerotic lesions. Pflugers Arch 2008; 455: 811-818.
    CrossrefPubMedGoogle Scholar
  • 20 Luttun A, Lutgens E, Manderveld A. et al. Loss of matrix metalloproteinase-9 or matrix metalloproteinase-12 protects apolipoprotein E-deficient mice against atherosclerotic media destruction but differentially affects plaque growth. Circulation 2004; 109: 1408-1414.
    CrossrefPubMedGoogle Scholar
  • 21 Konsti J, Lundin M, Joensuu H. et al. Development and evaluation of a virtual microscopy application for automated assessment of Ki-67 expression in breast cancer. BMC Clin Pathol 2011; 11: 3.
    CrossrefPubMedGoogle Scholar
  • 22 Fleenor BS, Seals DR, Zigler ML. et al. Superoxide-lowering therapy with TEMPOL reverses arterial dysfunction with aging in mice. Aging Cell 2012; 11: 269-276.
    CrossrefPubMedGoogle Scholar
  • 23 Van Hove CE, Van der Donkt C, Herman AG. et al. Vasodilator efficacy of nitric oxide depends on mechanisms of intracelllar calcium mobilisation in mouse aortic smooth muscle cells. Br J Pharmacol 2009; 158: 920-930.
    CrossrefPubMedGoogle Scholar
  • 24 Kang LS, Reyes RA, Muller-Delp JM. Aging impairs flow-induced dilation in coronary arterioles: role of NO and H(2)O(2). Am J Physiol Heart Circ Physiol 2009; 297: H1087-H1095.
    CrossrefPubMedGoogle Scholar
  • 25 Lentz SR, Tsiang M, Sadler JE. Regulation of thrombomodulin by tumor necrosis factor - comparison of transcriptional and posttranscriptional mechanisms. Blood 1991; 77: 542-550.
    CrossrefPubMedGoogle Scholar
  • 26 Kume M, Hayashi T, Yuasa H. et al. Bacterial lipopolysaccharide decreases thrombomodulin expression in the sinusoidal endothelial cells of rats: a possible mechanism of intrasinusoidal microthrombus formation and liver dysfunction. J Hepatol 2003; 38: 9-17.
    CrossrefPubMedGoogle Scholar
  • 27 Conway EM, Rosenberg RD. Tumor necrosis factor suppresses transcription of the thrombomodulin gene in endothelial cells. Mol Cell Biol 1988; 8: 5588-5592.
    CrossrefPubMedGoogle Scholar
  • 28 Rajan S, Ye J, Bai S. et al. NF-kappaB, but not p38 MAP kinase, is required for TNF-alpha-induced expression of cell adhesion molecules in endothelial cells. J Cell Biochem 2008; 105: 447-486.
    CrossrefPubMedGoogle Scholar
  • 29 Zhang H, Park Y, Wu J. et al. Role of TNF-alpha in vascular dysfunction. Clin Sci 2009; 116: 219-230.
    CrossrefPubMedGoogle Scholar
  • 30 Lesniewski LA, Durrant JR, Connell ML. et al. Salicylate treatment improves age-associated vascular endothelial dysfunction: potential role of nuclear factor kappaB and forkhead Box O phosphorylation. J Gerontol A Biol Sci Med Sci 2011; 66: 409-418.
    CrossrefPubMedGoogle Scholar
  • 31 Lesniewski LA, Durrant JR, Connell ML. et al. Aerobic exercise reverses arterial inflammation with aging in mice. Am J Physiol Heart Circ Physiol 2011; 301: H1025-H1032.
    CrossrefPubMedGoogle Scholar
  • 32 Stein S, Schäfer N, Breitenstein A. et al. SIRT1 reduces endothelial activation without affecting vascular function in ApoE-/- mice. Aging 2010; 2: 353-360.
    CrossrefPubMedGoogle Scholar
  • 33 Eiserich JP, Baldus S, Brennan ML. et al. Myeloperoxidase, a leukocyte-derived vascular NO oxidase. Science 2002; 296: 2391-2394.
    CrossrefPubMedGoogle Scholar
  • 34 Walker AE, Seibert SM, Donato AJ. et al. Vascular endothelial function is related to white blood cell count and myeloperoxidase among healthy middle-aged and older adults. Hypertension 2010; 55: 363-369.
    CrossrefPubMedGoogle Scholar