Intrauterine growth restriction delays cardiomyocyte maturation and alters coronary artery function in the fetal sheep

Abstract

There is now extensive evidence suggesting that intrauterine perturbations are linked with an increased risk of developing cardiovascular disease. Human epidemiological studies, supported by animal models, have demonstrated an association between low birth weight, a marker of intrauterine growth restriction (IUGR), and adult cardiovascular disease. However, little is known of the early influence of IUGR on the fetal heart and vessels. The aim of this study was to determine the effects of late gestational IUGR on coronary artery function and cardiomyocyte maturation in the fetus. IUGR was induced by placental embolization in fetal sheep from 110 to 130 days of pregnancy (D110-130); term approximately D147; control fetuses received saline. At necropsy (D130), wire and pressure myography was used to test endothelial and smooth muscle function, and passive mechanical wall properties, respectively, in small branches of left descending coronary arteries. Myocardium was dissociated for histological analysis of cardiomyocytes. At D130, IUGR fetuses (2.7 +/- 0.1 kg) were 28% lighter than controls (3.7 +/- 0.3 kg; P = 0.02). Coronary arteries from IUGR fetuses had enhanced responsiveness to the vasoconstrictors, angiotensin II and the thromboxane analogue U46619, than controls (P < 0.01). Endothelium-dependent and -independent relaxations were not different between groups. Coronary arteries of IUGR fetuses were more compliant (P = 0.02) than those of controls. The incidence of cardiomyocyte binucleation was lower in the left ventricles of IUGR fetuses (P = 0.02), suggestive of retarded cardiomyocyte maturation. We conclude that late gestational IUGR alters the reactivity and mechanical wall properties of coronary arteries and cardiomyocyte maturation in fetal sheep, which could have lifelong implications for cardiovascular function.

Figure 1

Analysis of cardiomyocytes in fetal sheep at D130 A, examples of mononucleated and binucleated cardiomyocytes. B, proportions of mononucleated and binucleated cardiomyocytes in LV and RV of control (n = 7) and IUGR fetuses (n = 8). C, cardiomyocyte area in LV and RV, control (LV n = 7, RV n = 7) and IUGR (LV n = 8, RV n = 5) groups. *P < 0.05 control versus IUGR; †P < 0.001 binucleated versus mononucleated; ‡P < 0.001 RV versus LV.

Figure 2

Contractile responses of coronary arteries from control and IUGR fetuses A, responses induced by AngII in coronary arteries from control (n = 8) and IUGR (n = 7) fetuses. P < 0.001 ANOVA. B, contractions evoked by U46619 in coronary arteries. *P < 0.05 ANOVA.

Figure 3

Endothelium-dependent relaxation in control and IUGR fetuses A, concentration–relaxation curves for bradykinin (BK) in absence and presence of l-NAME and indomethacin (Indo) for control (n = 7) and IUGR (n = 6) arteries. B, duration of endothelium-dependent relaxation in the absence and presence of l-NAME and Indo for control (n = 7) and IUGR (n = 6) arteries.*P < 0.05, ANOVA.

Figure 4

Passive mechanical wall properties of coronary arteries Stress–strain relationships for coronary arteries from IUGR (n = 8) and control (n = 8) fetuses. *P = 0.04, ANOVA.