Abstract 377: Neonatal Hyperoxia Contributes To Early Cardio-renal Fibrosis And Systemic Vascular Stiffness In 1 Year Old Rats

Abstract

Background: There is a knowledge gap in the mechanisms linking neonatal hyperoxia (O 2 ) exposure and its contribution to cardio-renal dysfunction in adults born preterm. TGF-β, a pro-fibrotic cytokine is a key player in cardio-renal fibrosis and vascular stiffness. Here, we test the hypothesis that neonatal hyperoxia induces cardio-renal dysfunction and systemic vascular stiffness in adulthood and this is associated with increased TGF-β levels. Objective: To determine the association between cardio-renal dysfunction, systemic vascular stiffness and TGF-β levels in adult rats exposed to neonatal hyperoxia. Methods: Newborn rats (N=22) randomly assigned to normoxia (RA) or hyperoxia (85% O 2 ) from postnatal day 1 to 14 (P1 to P14), were recovered in normoxic conditions until 1 year of life. At 1 year, left ventricular (LV) function was assessed by echocardiography. Aortic and mesenteric arterial stiffness was assessed by wire myography. RNA-seq of the aorta and kidney was done to assess the transcriptional effects of neonatal hyperoxia at 1 year. TGF-β expression was assessed by multiplex cytokine analysis in heart, aorta and kidney. Data was analyzed by Student’s T test. Results: At 1 year, there was no evidence of LV dysfunction in rats exposed to neonatal hyperoxia. In contrast, wire myography revealed that rats exposed to neonatal O 2 had significantly increased stiffness of mesenteric artery and aorta. Neonatal hyperoxia exposure differentially regulated genes in 1 year old aorta and kidney. Gene set enrichment analysis showed that genes most induced in the aorta by hyperoxia were “connective tissue development”, “extracellular matrix remodeling” and in the kidney were “actin cytoskeleton”, “epithelial cell differentiation”. As compared to the RA group, rats exposed to neonatal hyperoxia had significantly increased TGF-β1 and TGF-β2 expression in LV and increased TGF-β1 and similar TGF-β2 expression in kidney at 1 year of age. Conclusion: Although LV function was normal in hyperoxia-exposed 1 year old rats, these animals had increased systemic vascular stiffness and increased TGF-β expression in LV, aorta and kidney, implying the crucial role of TGF-β signaling in cardio-renal dysfunction in adult rodents exposed to neonatal hyperoxia.