Skip to main content Accessibility help
×
Home

Increased collagen deposition in the heart of chronically hypoxic ovine fetuses

  • J. A. Thompson (a1) (a2), K. Piorkowska (a1) (a2), R. Gagnon (a3), B. S. Richardson (a1) (a2) (a4) and T. R. H. Regnault (a1) (a2) (a4)...

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.

Copyright

Corresponding author

*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

References

Hide All
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, 1103.
2.Raphael, D. The health of Canada's children. Part I: Canadian children's health in comparative perspective. Paediatr Child Health. 2010; 15, 2329.
3.Bahtiyar, MO, Copel, JA. Cardiac changes in the intrauterine growth-restricted fetus. Semin Perinatol. 2008; 32, 190193.
4.Crispi, F, Bijnens, B, Figueras, F, et al. Fetal growth restriction results in remodeled and less efficient hearts in children. Circulation. 2010; 121, 24272436.
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, 630672.
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, H2001H2008.
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, 3543.
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, 639648.
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, R306R313.
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, 155159.
11.Barker, DJP, Osmond, C, Winter, PD, Margetts, B. Weight in infancy and death from ischaemic heart disease. The Lancet. 1998; 2, 577580.
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, H1364H1372.
13.Czuriga, D, Paulus, WJ, Czuriga, I, et al. Cellular mechanisms for diastolic dysfunction in the human heart. Curr Pharm Biotechno. 2012; 13, 25322538.
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, 218223.
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, 4350.
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, H424H432.
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, 483490.
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, 477490.
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, 33193332.
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, 4751.
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), 453458.
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.
23.Ghidini, A. Idiopathic fetal growth restriction: a pathophysiologic approach. Obstet Gynecol Surv. 1996; 51, 376382.
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, 15341542.
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, 807812.
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, 109125.
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, 952961.
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, 430436.
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, 274280.
30.Takumi, M. Doppler echocardiographic studies of diastolic cardiac function in the human fetal heart. Kurume Med J. 2001; 48, 5964.
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, 605610.
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, H2861H2870.
33.Pacher, P, Beckman, JS, Liaudet, L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev. 2007; 87, 315424.
34.Shah, AM, McDermott, BJ, Grieve, DJ. Nox2 NADPH oxidase promotes pathologic cardiac remodeling associated with doxorubicin chemotherapy. Cancer Res. 2010; 70, 92879297.
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, 2531.

Keywords

Type Description Title
PDF
Supplementary materials

Thompson Supplementary Material
Appendix

 PDF (52 KB)
52 KB

Increased collagen deposition in the heart of chronically hypoxic ovine fetuses

  • J. A. Thompson (a1) (a2), K. Piorkowska (a1) (a2), R. Gagnon (a3), B. S. Richardson (a1) (a2) (a4) and T. R. H. Regnault (a1) (a2) (a4)...

Metrics

Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed