Cardiac Renin-Angiotensin Signaling and Susceptibility to Extracellular Matrix Remodeling in Male Mouse Offspring Conceived by In Vitro Fertilization

Assisted reproductive technology (ART) has been associated with increased cardiovascular risk in offspring, but the underlying mechanisms remain unclear. This study investigated whether alterations in the cardiac renin-angiotensin system (RAS) are associated with increased susceptibility to myocardial fibrosis in offspring conceived via in vitro fertilization (IVF). Bioinformatics analysis and in vivo experiments were integrated. Cardiac transcriptomic data from IVF offspring (GSE211597) were analyzed to identify differentially expressed genes (DEGs), followed by enrichment and protein-protein interaction (PPI) analyses. An IVF mouse model was established and subjected to a high-fat diet (HFD) as "a second hit". Metabolic parameters, cardiac histology, and expression of RAS- and fibrosis-related molecules were assessed. The angiotensin II type 1 receptor (AT1R) antagonist Candesartan was used to evaluate the functional involvement of RAS signaling. Transcriptomic analysis revealed significant alterations in metabolic and extracellular matrix (ECM)-related pathways, with Agt identified as a central hub gene. Under HFD, IVF offspring exhibited aggravated metabolic dysfunction and increased myocardial collagen deposition. Increased expression of angiotensinogen (AGT), AT1R, collagen type I alpha 1 chain (COL1A1), and collagen type I alpha 2 chain (COL1A2) suggested alterations in cardiac RAS signaling accompanied by extracellular matrix (ECM) remodeling. Candesartan partially improved metabolic abnormalities and attenuated RAS- and fibrosis-related molecular changes. IVF is associated with increased susceptibility to cardiac ECM remodeling under metabolic stress, accompanied by alterations in cardiac RAS-related signaling. Pharmacological blockade of AT1R partially attenuated these changes, suggesting a functional contribution of RAS signaling. These findings provide mechanistic insight into developmental origins of health and disease (DOHaD)-related cardiovascular risk and suggest that RAS signaling may represent a potential therapeutic target.