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Increased collagen deposition in the heart of chronically hypoxic ovine fetuses

Published online by Cambridge University Press:  02 July 2013

J. A. Thompson ,
K. Piorkowska ,
R. Gagnon ,
B. S. Richardson  and
T. R. H. Regnault
J. A. Thompson*
Affiliation:
Department of Physiology and Pharmacology, Western University, Ontario, London, Ontario, Canada Children's Health Research Institute (CHRI), Lawson Health Research Institute, Western University, Ontario, London, Ontario, Canada
K. Piorkowska
Affiliation:
Department of Physiology and Pharmacology, Western University, Ontario, London, Ontario, Canada Children's Health Research Institute (CHRI), Lawson Health Research Institute, Western University, Ontario, London, Ontario, Canada
R. Gagnon
Affiliation:
Department of Obstetrics and Gynaecology, McGill University, Montreal, Quebec, Canada
B. S. Richardson
Affiliation:
Department of Physiology and Pharmacology, Western University, Ontario, London, Ontario, Canada Children's Health Research Institute (CHRI), Lawson Health Research Institute, Western University, Ontario, London, Ontario, Canada Department of Obstetrics and Gynecology, Western University, Ontario, London, Ontario, Canada
T. R. H. Regnault
Affiliation:
Department of Physiology and Pharmacology, Western University, Ontario, London, Ontario, Canada Children's Health Research Institute (CHRI), Lawson Health Research Institute, Western University, Ontario, London, Ontario, Canada Department of Obstetrics and Gynecology, Western University, Ontario, London, Ontario, Canada
*
*Address for correspondence: J. A. Thompson, Dental Sciences Building RM 2027, Western University, 1151 Richmond St. London, Ontario, Canada N6A 3K7. Email jathomps@uwo.ca
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Abstract

This study determined the effect of chronic intrauterine hypoxia on collagen deposition in the fetal sheep heart. Moderate or severe hypoxia was induced by placental embolization in chronically catheterized fetal sheep for 15 days starting at gestational day 116 ± 2 (term ∼147 days). The fetal right and left ventricle were evaluated for collagen content using a Sirius red dye and for changes in signaling components of pathways involved in collagen synthesis and remodeling using quantitative polymerase chain reaction and Western blot. In severely hypoxic fetuses (n = 6), there was a two-fold increase (P < 0.05) in the percentage staining for collagen in the right ventricle, compared with control (n = 6), whereas collagen content was not altered in the moderate group (n = 4). Procollagen I and III mRNA levels were increased in the right ventricle, two-fold (P < 0.05) and three-fold (P < 0.05), respectively, in the severe group relative to control. These changes were paralleled by a two-fold increase (P < 0.05) in mRNA levels of the pro-fibrotic cytokine, transforming growth factor β (TGF-β1), in the right ventricle. In the right ventricle, the mRNA levels of matrix metalloproteinase 2 (MMP-2) and its activator, membrane-type MMP (MTI-MMP) were increased five-fold (P = 0.06) and three-fold (P < 0.05), respectively, relative to control. Protein levels of TGF-β were increased in the left ventricle (P < 0.05). Thus, up-regulated collagen synthesis leading to increased collagen content occurs in the chronically hypoxic fetal heart and may contribute to the right ventricular diastolic and systolic dysfunction reported in human intrauterine growth restriction fetuses.

Keywords

hearthypoxiaplacental insufficiency
Type
Original Article
Information
Journal of Developmental Origins of Health and Disease , Volume 4 , Issue 6 , December 2013 , pp. 470 - 478
Copyright
Copyright © Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2013 

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References

1.Martin, JA, Hamilton, BE, Sutton, PD, et al. Centers for Disease Control and Prevention National Center for Health Statistics National Vital Statistics System. Natl Vital Stat Rep. 2007; 56, 1–103.Google Scholar
2.Raphael, D. The health of Canada's children. Part I: Canadian children's health in comparative perspective. Paediatr Child Health. 2010; 15, 23–29.CrossRefGoogle ScholarPubMed
3.Bahtiyar, MO, Copel, JA. Cardiac changes in the intrauterine growth-restricted fetus. Semin Perinatol. 2008; 32, 190–193.Google Scholar
4.Crispi, F, Bijnens, B, Figueras, F, et al. Fetal growth restriction results in remodeled and less efficient hearts in children. Circulation. 2010; 121, 2427–2436.CrossRefGoogle ScholarPubMed
5.Gagnon, R, Johnston, L, Murotsuki, J. Fetal placental embolization in the late-gestation ovine fetus: alterations in umbilical blood flow and fetal heart rate patterns. Am J Obstet Gynecol. 1996; 175, 630–672.CrossRefGoogle ScholarPubMed
6.Gagnon, R, Lamb, T, Richardson, BS. Cerebral circulatory responses of near-term ovine fetuses during sustained fetal placental embolization. Am J Physiol Heart Circ Physiol. 1997; 42, H2001–H2008.CrossRefGoogle Scholar
7.Kingdom, J, Huppertz, B, Seaward, G, Kaufmann, P. Development of the placenta villous tree and its consequences for fetal growth. Eur J Obstet Gynecol. 2000; 92, 35–43.CrossRefGoogle ScholarPubMed
8.Louey, S, Jonker, SS, Giraud, GD, Thornburg, KL. Placental insufficiency decreases cell cycle activity and terminal maturation in fetal sheep cardiomyocytes. J Physiol. 2007; 15, 639–648.Google Scholar
9.Morrison, JL, Botting, KJ, Dyer, JL, et al. Restriction of placental function alters heart development in the sheep fetus. Am J Physiol Regul Integr Comp Physiol. 2007; 293, R306–R313.Google Scholar
10.Rizzo, G, Capponi, A, Cavicchioni, O, Vendola, M, Arduini, D. Low cardiac output to the placenta: an early hemodynamic adaptive mechanism in intrauterine growth restriction. Ultrasound Obstet Gynecol. 2008; 32, 155–159.Google Scholar
11.Barker, DJP, Osmond, C, Winter, PD, Margetts, B. Weight in infancy and death from ischaemic heart disease. The Lancet. 1998; 2, 577–580.Google Scholar
12.Graham, HK, Trafford, AW. Spatial disruption and enhanced degradation of collagen with the transition from compensated ventricular hypertrophy to symptomatic congestive heart failure. Am J Physiol. 2007; 292, H1364–H1372.Google ScholarPubMed
13.Czuriga, D, Paulus, WJ, Czuriga, I, et al. Cellular mechanisms for diastolic dysfunction in the human heart. Curr Pharm Biotechno. 2012; 13, 2532–2538.Google Scholar
14.Chen, L, Zhang, J, Gan, TX, et al. Left ventricular dysfunction and associated cellular injury in rats exposed to chronic intermittent hypoxia. J Appl Physiol. 2008; 104, 218–223.Google Scholar
15.Zhao, W, Zhao, T, Chen, Y, Ahokas, RA, Sun, Y. Oxidative stress mediates cardiac fibrosis by enhancing transforming growth factor-beta1 in hypertensive rats. Mol Cell Biochem. 2008; 317, 43–50.Google Scholar
16.Lucas, JA, Zhang, Y, Kaizheng, PL, et al. Inhibition of transforming growth factor-β signaling induces left ventricular dilation and dysfunction in the pressure overloaded heart. Am J Physiol Heart Circ Physiol. 2010; 298, H424–H432.Google Scholar
17.Kai, H, Kuwahara, F, Tokuda, K, Imaizumi, T. Diastolic dysfunction in hypertensive hearts: role of perivascular inflammation and reactive myocardial fibrosis. Hypertens Res. 2005; 28, 483–490.Google Scholar
18.Ross, JJ, Tranquillo, RT. ECM gene expression correlates with in vitro tissue growth and development in fibrin gel remodeled by neonatal smooth muscle cells. Matrix Biol. 2003; 22, 477–490.CrossRefGoogle ScholarPubMed
19.Thompson, JA, Richardson, BS, Gagnon, R, Regnault, TRH. Chronic hypoxia interferes with aortic development in the late gestation ovine fetus. J Physiol. 2011; 589, 3319–3332.Google Scholar
20.Lee, DA, Assoku, E, Doyle, V. A specific quantitative assay for collagen synthesis by cells seeded in collagen-based biomaterials using Sirius red F3B precipitation. J Mater Sci Mater Med. 1998; 9, 47–51.CrossRefGoogle ScholarPubMed
21.Cowell, S, Knauper, V, Stewart, ML. Induction of matrix metalloproteinase activation cascades based on membrane-type matrix metalloproteinase: associated activation of gelantinase A, gelatinase B and collagenase 3. Biochem J. 1998; 331(Pt. 2), 453–458.Google Scholar
22.Nakerakanti, SS, Bujor, AM, Trojanowska, M. CCN2 is required for the TGF-β Induced Activation of Smad1 – Erk1/2 Signaling Network. PLoS One. 2001; 6, e21911.CrossRefGoogle Scholar
23.Ghidini, A. Idiopathic fetal growth restriction: a pathophysiologic approach. Obstet Gynecol Surv. 1996; 51, 376–382.CrossRefGoogle ScholarPubMed
24.Krebs, C, Macara, LM, Leiser, R, Bowman, AW, et al. Intrauterine growth restriction with absent end-diastolic flow velocity in the umbilical artery is associated with maldevelopment of the placental villous tree. Am J Obstet Gynecol. 1996; 175, 1534–1542.Google Scholar
25.Macara, L, Kingdom, JC, Kohnen, G, et al. Elaboration of stem villous vessels in growth restricted pregnancies with abnormal umbilical artery Doppler waveforms. Br J Obstet Gynaecol. 1995; 102, 807–812.Google Scholar
26.Adler, CP, Costabel, U. Myocardial DNA and cell number under the influence of cytostatics. I. Post mortem investigations of human hearts. Virchows Arch B Cell Pathol Incl Mol Pathol. 1908; 32, 109–125.Google Scholar
27.Burrell, JH, Boyn, AM, Kumarasamy, V, et al. Growth and maturation of cardiac myocytes in fetal sheep in the second half of gestation. Anat Rec A Discov Mol Cell Evol Biol. 2003; 274, 952–961.CrossRefGoogle ScholarPubMed
28.Hernandez-Andrade, E, Crispi, F, Benavides-Serralde, JA, et al. Contribution of the myocardial performance index and aortic isthmus blood flow index to predicting mortality in preterm growth-restricted fetuses. UltrasoundObstet Gynecol. 2009; 34, 430–436.Google Scholar
29.Benavides-Serralde, A, Scheier, M, Cruz-Martinez, R, et al. Changes in central and peripheral circulation in intrauterine growth-restricted fetuses at different stages of umbilical artery flow deterioration: new fetal cardiac and brain parameters. Gynecol Obstet Invest. 2011; 71, 274–280.Google Scholar
30.Takumi, M. Doppler echocardiographic studies of diastolic cardiac function in the human fetal heart. Kurume Med J. 2001; 48, 59–64.Google Scholar
31.Arduini, D, Rizzo, G, Romanini, C. Changes of pulsatility index from fetal vessels preceding the onset of late decelerations in growth retarded fetuses. Obstet Gynecol. 1992; 79, 605–610.Google Scholar
32.Zahradka, P, Harding, G, Litchie, B, et al. Activation of MMP-2 in response to vascular injury is mediated by phosphatidylinositol 3-kinase-dependent-expression of MTI-MMP. Am J Physiol Heart Circ Physiol. 2004; 287, H2861–H2870.Google Scholar
33.Pacher, P, Beckman, JS, Liaudet, L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev. 2007; 87, 315–424.Google Scholar
34.Shah, AM, McDermott, BJ, Grieve, DJ. Nox2 NADPH oxidase promotes pathologic cardiac remodeling associated with doxorubicin chemotherapy. Cancer Res. 2010; 70, 9287–9297.Google Scholar
35.Evans, LC, Liu, H, Pinkas, GA, Thompson, LP. Chronic hypoxia increases peroxynitrite, MMP-9 expression and collagen accumulation in fetal guinea pig hearts. Pediatr Res. 2011; 71, 25–31.Google Scholar
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