Progressive Left Ventricular Pressure Overload Reprograms Neonatal Left Ventricular Development via Sustained Proliferation, Metabolic Arrest, and Compensatory Angiogenesis
Progressive left ventricular pressure overload in neonatal rats reprograms heart development by sustaining cardiomyocyte proliferation and altering metabolic pathways.
Where it sits
this study against the rest of the p21 (p021) corpusSummary and findings
This study investigated the effects of progressive left ventricular pressure overload (LVPO) on neonatal rat heart development using abdominal aortic banding surgery. The researchers observed changes in gene expression related to cardiomyocyte proliferation and metabolic pathways. Notably, 100% survival was achieved in the neonatal rat model.
Abstract
Left ventricular pressure overload (LVPO) is a common hemodynamic stressor in pediatric cardiovascular diseases, yet how progressive—rather than fixed—overload reshapes the neonatal left ventricular (LV) developmental program remains largely unexplored. In this study, we established a neonatal rat model of progressive LVPO via abdominal aortic banding surgery (ABS) on postnatal day 1(P1), achieving 100% survival. Model validation was confirmed by abdominal ultrasound and serial blood pressure monitoring from P21 to P35, demonstrating sustained increases in flow velocity and arterial pressures. To investigate the transcriptomic impact of progressive overload, we performed RNA-sequencing on LV free walls at P3 and P7. The total number of differentially expressed genes (DEGs) between P7 and P3 was comparable between normal development (2,927 DEGs) and overload conditions (3,132 DEGs); however, principal component analysis revealed a marked shift in the LV developmental trajectory under overload, indicating qualitative reprogramming. Among 1,550 shared DEGs, enrichment for cardiac proliferation was observed, yet the cellular phenotypes diverged: normal development exhibited declining Ki67⁺ cardiomyocytes, whereas overload progressively increased proliferation. Importantly, 1,377 DEGs unique to normal development were enriched in oxidative phosphorylation and metabolic pathways, suggesting that overload blunts normal maturational cues. Conversely, 1,582 DEGs exclusively expressed under overload were enriched in angiogenesis and VEGF signaling, with validated upregulation of Adam8, Dll1, and Ptgs2. Collectively, our findings demonstrate that progressive LVPO does not simply damage the neonatal heart but actively reprograms LV development by sustaining cardiomyocyte proliferation via metabolic maturation arrest, extinguishing normal maturation, and inducing compensatory angiogenesis.