Fetal growth restriction and the programming of heart growth and cardiac insulin‐like growth factor 2 expression in the lamb

Non‐Technical Summary Cardiovascular disease is responsible for 30% of deaths worldwide and epidemiological data demonstrate that poor growth before birth is associated with an increased risk of heart disease in adult life. We show that in response to reduced placental substrate supply there is an increase in cardiac insulin‐like growth factor‐2 (IGF‐2) and the IGF‐2 receptor (IGF‐2R) in the fetus. Importantly, this effect is programmed because it is also present after birth in the lamb at 21 days of age. We also show that the increase in IGF‐2 and IGF‐2R gene expression is not epigenetically regulated through the IGF‐2/H19 or IGF‐2R methylation process. This study places the IGF‐2 receptor signalling pathway as a prime candidate for mediating cardiac hypertrophy in fetal growth restriction before and after birth. Reduced growth in fetal life together with accelerated growth in childhood, results in a ∼50% greater risk of coronary heart disease in adult life. It is unclear why changes in patterns of body and heart growth in early life can lead to an increased risk of cardiovascular disease in adulthood. We aimed to investigate the role of the insulin‐like growth factors in heart growth in the growth‐restricted fetus and lamb. Hearts were collected from control and placentally restricted (PR) fetuses at 137–144 days gestation and from average (ABW) and low (LBW) birth weight lambs at 21 days of age. We quantified cardiac mRNA expression of IGF‐1, IGF‐2 and their receptors, IGF‐1R and IGF‐2R, using real‐time RT‐PCR and protein expression of IGF‐1R and IGF‐2R using Western blotting. Combined bisulphite restriction analysis was used to assess DNA methylation in the differentially methylated region (DMR) of the IGF‐2/H19 locus and of the IGF‐2R gene. In PR fetal sheep, IGF‐2, IGF‐1R and IGF‐2R mRNA expression was increased in the heart compared to controls. LBW lambs had a greater left ventricle weight relative to body weight as well as increased IGF‐2 and IGF‐2R mRNA expression in the heart, when compared to ABW lambs. No changes in the percentage of methylation of the DMRs of IGF‐2/H19 or IGF‐2R were found between PR and LBW when compared to their respective controls. In conclusion, a programmed increased in cardiac gene expression of IGF‐2 and IGF‐2R may represent an adaptive response to reduced substrate supply (e.g. glucose and/or oxygen) in order to maintain heart growth and may be the underlying cause for increased ventricular hypertrophy and the asso