Hostname: page-component-78c5997874-8bhkd Total loading time: 0 Render date: 2024-11-10T20:45:35.103Z Has data issue: false hasContentIssue false
  • English
  • Français

Prenatal stress enhances severity of atherosclerosis in the adult apolipoprotein E-deficient mouse offspring via inflammatory pathways

Published online by Cambridge University Press:  01 November 2012

H. Ho ,
S. Lhotak ,
M. E. Solano ,
K. Karimi ,
M. K. Pincus ,
R. C. Austin  and
P. Arck
H. Ho
Affiliation:
Department of Medicine, Brain-Body-Institute, McMaster University, Hamilton, Ontario, Canada
S. Lhotak
Affiliation:
Department of Medicine, Division of Nephrology, St. Joseph's Healthcare Hamilton, McMaster University, Ontario, Canada
M. E. Solano
Affiliation:
Department of Obstetrics and Fetal Medicine, Laboratory for Experimental Fetomaternal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
K. Karimi
Affiliation:
Department of Medicine, Brain-Body-Institute, McMaster University, Hamilton, Ontario, Canada
M. K. Pincus
Affiliation:
Department of Pediatrics, Division of Pneumology and Immunology, Charité University Medical Center, Berlin, Germany
R. C. Austin
Affiliation:
Department of Medicine, Division of Nephrology, St. Joseph's Healthcare Hamilton, McMaster University, Ontario, Canada
P. Arck*
Affiliation:
Department of Obstetrics and Fetal Medicine, Laboratory for Experimental Fetomaternal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
*
*Address for correspondence: Dr P. Arck, MD, Labor fuer Experimentelle Feto-Maternale Medizin, Klinik für Geburtshilfe und Praenatalmedizin, Martinistr, 52, 20246 Hamburg, Germany. Email p.arck@uke.de
Get access Rights & Permissions [Opens in a new window]

Abstract

Atherosclerosis is the underlying cause of cardiovascular disease and stroke. Endothelial cell dysfunctions are early events in atherosclerosis, resulting in the recruitment of circulating monocytes. The immune system can elicit an inflammatory response toward the atherosclerotic lesion, thereby accelerating lesion growth. Risk factors for atherosclerosis include hypertension, smoking, stress perception or low birth weight. As prenatal stress challenge decreases the birth weight and affects the offspring's postnatal immune response, we aimed to investigate whether prenatal stress contributes to the development of atherosclerosis in mice. Syngenic pregnant apolipoprotein E-deficient (apoE−/−) dams were exposed to sound stress on gestation days 12.5 and 14.5. The presence and size of atherosclerotic plaques in the offspring at the age of 15 weeks was evaluated by histomorphology, accompanied by flow cytometric analysis of the frequency and phenotype of monocytes/macrophages and regulatory T (Treg) cells in the blood. Further, cytokine secretion of peripheral blood lymphocytes was analyzed. In response to prenatal stress challenge, an increased frequency of large atherosclerotic plaques was detectable in apoE−/− offspring, which was particularly profound in females. Prenatal stress also resulted in alterations of the offspring's immune response, such as a decreased frequency of Treg cells in blood, alterations of macrophage populations in blood and an increased secretion of inflammatory cytokines. We provide novel evidence that prenatally stressed adult offspring show an increased severity of atherosclerosis. As Treg cells are key players in dampening inflammation, the observed increase in atherosclerosis may be due to the lack of Treg cell frequency. Future interdisciplinary research is urgently required to understand the developmental origin of prenatal stress-induced atherosclerosis. The availability of our model may facilitate and foster such research endeavors.

Keywords

apoE−/−atherosclerosisinflammationplaquesprenatal stress
Type
Original Article
Information
Journal of Developmental Origins of Health and Disease , Volume 4 , Issue 1 , February 2013 , pp. 90 - 97
Copyright
Copyright © Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2012 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1.Glass, CK, Witztum, JL. Atherosclerosis. The road ahead. Cell. 2001; 104, 503–516.CrossRefGoogle ScholarPubMed
2.Amarenco, P, Cohen, A, Tzourio, C, et al. Atherosclerotic disease of the aortic arch and the risk of ischemic stroke. N Engl J Med. 1994; 331, 1474–1479.Google Scholar
3.Trzos, E, Uznanska, B, Rechcinski, T, et al. Myocardial infarction in young people. Cardiol J. 2009; 16, 307–311.Google ScholarPubMed
4.Tian, N, Penman, AD, Mawson, AR, Manning, RD Jr, Flessner, MF. Association between circulating specific leukocyte types and blood pressure: the atherosclerosis risk in communities (ARIC) study. J Am Soc Hypertens. 2010; 4, 272–283.Google Scholar
5.Zoccali, C, Seck, S. What makes plaques vulnerable in CKD?: a fresh look at metalloproteinases. Kidney Int. 2010; 78, 1206–1208.CrossRefGoogle Scholar
6.Hackam, DG, Anand, SS. Emerging risk factors for atherosclerotic vascular disease: a critical review of the evidence. JAMA. 2003; 290, 932–940.CrossRefGoogle ScholarPubMed
7.Kavey, RE, Daniels, SR, Lauer, RM, et al. American Heart Association guidelines for primary prevention of atherosclerotic cardiovascular disease beginning in childhood. Circulation. 2003; 107, 1562–1566.Google Scholar
8.Leduc, L, Levy, E, Bouity-Voubou, M, Delvin, E. Fetal programming of atherosclerosis: possible role of the mitochondria. Eur J Obstet Gynecol Reprod Biol. 2010; 149, 127–130.CrossRefGoogle ScholarPubMed
9.Libby, P, Ridker, PM, Maseri, A. Inflammation and atherosclerosis. Circulation. 2002; 105, 1135–1143.Google Scholar
10.Hansson, GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005; 352, 1685–1695.Google Scholar
11.Stary, HC, Blankenhorn, DH, Chandler, AB, et al. A definition of the intima of human arteries and of its atherosclerosis-prone regions. Circulation. 1992; 85, 391–405.Google Scholar
12.Barker, DJ. In utero programming of chronic disease. Clin Sci (Lond). 1998; 95, 115–128.CrossRefGoogle ScholarPubMed
13.McGill, HC Jr, McMahan, CA, Herderick, EE, et al. Origin of atherosclerosis in childhood and adolescence. Am J Clin Nutr. 2000; 72 (Suppl 5), 1307S–1315S.CrossRefGoogle ScholarPubMed
14.Palinski, W, Napoli, C. The fetal origins of atherosclerosis: maternal hypercholesterolemia, and cholesterol-lowering or antioxidant treatment during pregnancy influence in utero programming and postnatal susceptibility to atherogenesis. FASEB J. 2002; 16, 1348–1360.Google Scholar
15.Goharkhay, N, Sbrana, E, Gamble, PK, et al. Characterization of a murine model of fetal programming of atherosclerosis. Am J Obstet Gynecol. 2007; 197, e411–e415.Google Scholar
16.Knackstedt, MK, Hamelmann, E, Arck, PC. Mothers in stress: consequences for the offspring. Am J Reprod Immunol. 2005; 54, 63–69.CrossRefGoogle ScholarPubMed
17.Pincus-Knackstedt, MK, Joachim, RA, Blois, SM, et al. Prenatal stress enhances susceptibility of murine adult offspring toward airway inflammation. J Immunol. 2006; 177, 8484–8492.CrossRefGoogle ScholarPubMed
18.Andersson, IJ, Jiang, YY, Davidge, ST. Maternal stress and development of atherosclerosis in the adult apolipoprotein E-deficient mouse offspring. Am J Physiol Regul Integr Comp Physiol. 2009; 296, R663–R671.Google Scholar
19.Paigen, B, Morrow, A, Holmes, PA, Mitchell, D, Williams, RA. Quantitative assessment of atherosclerotic lesions in mice. Atherosclerosis. 1987; 68, 231–240.CrossRefGoogle ScholarPubMed
20.Dickhout, JG, Lhoták, Š, Hilditch, BA, et al. Induction of the unfolded protein response after monocyte to macrophage differentiation augments cell survival in early atherosclerotic lesions. FASEB J. 2011; 25, 576–589.Google Scholar
21.Solovjov, DA, Pluskota, E, Plow, EF. Distinct roles for the alpha and beta subunits in the functions of integrin alphaMbeta2. J Biol Chem. 2005; 280, 1336–1345.Google Scholar
22.Leenen, PJ, de Bruijn, MF, Voerman, JS, Campbell, PA, van Ewijk, W. Markers of mouse macrophage development detected by monoclonal antibodies. J Immunol Methods. 1994; 174, 5–19.Google Scholar
23.Davignon, D, Martz, E, Reynolds, T, Kurzinger, K, Springer, TA. Lymphocyte function-associated antigen 1 (LFA-1): a surface antigen distinct from Lyt-2,3 that participates in T lymphocyte-mediated killing. Proc Natl Acad Sci. 1981; 78, 4535–4539.CrossRefGoogle Scholar
24.Whitman, SC. A practical approach to using mice in atherosclerosis research. Clin Biochem Rev. 2004; 25, 81–93.Google Scholar
25.Kiecolt-Glaser, JK, Glaser, R, Gravenstein, S, Malarkey, WB, Sheridan, J. Chronic stress alters the immune response to influenza virus vaccine in older adults. Proc Natl Acad Sci. 1996; 93, 3043–3047.CrossRefGoogle ScholarPubMed
26.Kop, WJ. Chronic and acute psychological risk factors for clinical manifestations of coronary artery disease. Psychosom Med. 1999; 61, 476–487.Google Scholar
27.Everson, SA, Lynch, JW, Chesney, MA, et al. Interaction of workplace demands and cardiovascular reactivity in progression of carotid atherosclerosis: population based study. BMJ. 1997; 314, 553–558.Google Scholar
28.Kaplan, JR, Manuck, SB, Clarkson, TB, Lusso, FM, Taub, DM. Social status, environment, and atherosclerosis in cynomolgus monkeys. Arteriosclerosis. 1982; 2, 359–368.CrossRefGoogle ScholarPubMed
29.Chen, E, Hanson, MD, Paterson, LQ, et al. Socioeconomic status and inflammatory processes in childhood asthma: the role of psychological stress. J Allergy Clin Immunol. 2006; 117, 1014–1020.Google Scholar
30.Hansson, GK, Hermansson, A. The immune system in atherosclerosis. Nat Immunol. 2011; 12, 204–212.Google Scholar
31.Nakashima, Y, Raines, EW, Plump, AS, Breslow, JL, Ross, R. Upregulation of VCAM-1 and ICAM-1 at atherosclerosis-prone sites on the endothelium in the ApoE-deficient mouse. Arterioscler Thromb Vasc Biol. 1998; 18, 842–851.Google Scholar
32.Blois, S, Tometten, M, Kandil, J, et al. Intercellular adhesion molecule-1/LFA-1 cross talk is a proximate mediator capable of disrupting immune integration and tolerance mechanism at the feto-maternal interface in murine pregnancies. J Immunol. 2005; 174, 1820–1829.CrossRefGoogle ScholarPubMed