Intra-placental gene transfer of Insulin Like Growth Factor 1 Reprograms Altered Myocardial Gene Expression In Growth Restricted Mouse Model with Cardiac Dysfunction

Background: Intrauterine growth restriction (IUGR), defined as birth weight <10% for gestational age, is a risk factor for adult onset cardiovascular disease. We demonstrated that Intraplacental gene transfer of adenoviral insulin growth factor1 (Ad IGF1) rescues IUGR induced cardiac dysfunction in a surgical IUGR mouse model. The underlying molecular mechanism is unknown. We hypothesize that Ad IGF1 reprograms altered gene expression involved in collagen deposition in myocardium (Col1A1, CTGF, SRF, OPN, TGFβ) Method: Laparotomy was performed on pregnant C57 mice at embryonic day 18 and pups were divided into 3 groups. Control: Sham operated; IUGR: by ligation of a uterine artery branch; IUGR+IGF1: injection of Ad IGF1 after ligation. Pups were delivered and followed up with cross-sectional (2D) and Doppler transthoracic echocardiography until 36 week. Hearts were collected and RNA extracted for gene expression analysis by qPCR at 36 week. Data were analyzed using ANOVA Result: At week 36, IUGR mice showed significantly reduced EF (41 ± 6 vs 53 ± 7 vs 57 ± 9) compared to SHAM & IUGR+IGF1 (Fig A). IUGR showed significantly increased LVID;d (3.8 ± 0.3 vs 3.1± 0.49 vs 2.9 ± 0.4) as compared to SHAM & IUGR+IGF1 (Fig B). IUGR hearts demonstrated significantly increased CTGF (1.7± 0.6 vs 0.9 ± 0.3 vs 0.8 ± 0.2), and Col1A1 (2.4 ± 0.2 vs. 1.6 ± 0.4 vs 1.4 ± 0.5), as compared to SHAM & IUGR+IGF1(Fig C). No differences were detected in the other genes Conclusion: AdIGF1 gene transfer rescues IUGR induced cardiac dysfunction and reprograms myocardial gene expression of CTGF&COL1A1. These changes may represent a potential epigenetic regulation that reprograms the fetus and attenuates the risk of adult onset CVD