Mismatched Pre-and Postnatal Nutrition Leads To Pulmonary Vascular Dysfunction In Adulthood

Objective:Epidemiological and experimental studies have shown that undernutrition in the intrauterine and infant period can increase the risk of pulmonary arterial hypertension (PAH) and pulmonary vascular remodeling in adulthood. The dietary strategy and growth pattern in these two periods may have long-term effects on the onset and development of cardiovascular disease. By creating intrauterine growth retardation (IUGR) and intrauterine and postnatal growth retardation (IPGR) animal model induced by perinatal dietary restriction, our work aims to explore whether IUGR followed with postnatal dietary intervention can decrease the risk of PAH in adulthood and how PAH related gene takes part in this process epigenetically.Methods:1. Animal model:Female Sprague-Dawley (SD) rats were confirmed pregnancy by the presence of a vaginal smear plug. Pregnant rats were fed with standard chow ad libitum or50%of the ad libitum intake during the entire pregnancy. The pups born to the food restricted mothers were cross-fostered either by a mother who continued to be food restricted (IPGR) or by a control mother (IUGR). The pups born to control mothers were reared by control mother (Control). Only male offspring were studied later.2. Assessment of pulmonary arterial pressure and pulmonary vascular remodeling were made in14weeks male SD rats.3. Real-time PCR was used to analyze eNOS gene expression in lung tissue;4. Chromatin immunoprecipitation (ChIP) was used for the analysis of histone modification in gene promoter. Results:1. Weight:a) Birth weight comparison:mother food restricted (MFR) group was lower than Control group significantly.b)21days and14weeks weight comparison:significant difference was found among three groups (Control>IUGR> IPGR).2. Mean pulmonary arterial pressure (mPAP):IUGR rats were significantly higher than Control. IPGR group showed decreased mPAP in comparison with IUGR group.3. Pulmonary artery medial thickness is significantly higher in IUGR rats in comparison with Control. IPGR rats showed decreased pulmonary artery medial thickness compared with IUGR rats.4. eNOS expression in lung tissue was increased in IUGR group compared with Control groups. IPGR group showed decreased expression in comparison with IUGR group.5. Histone modification in eNOS promoter:histone3lysine9trimethylation was increased in both IUGR and IPGR groups.Conclusion:IUGR male rats have an increased risk of pulmonary arterial dysfunction with higher pulmonary arterial pressure in adulthood, while IUGR rats followed with postnatal food restriction decreased this risk. eNOS expression may be involved in the pathogenesis of PAH in this model. The epigenetic mechanism of eNOS upregulation still remains unknown.