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Premature infants are often exposed to hyperoxia. However, there is a lack of knowledge of the mechanistic underpinnings linking neonatal hyperoxia exposure and its contribution to cardio-renal dysfunction in adults born preterm. Our objective was to determine whether neonatal hyperoxia induces systemic vascular stiffness and cardio-renal dysfunction in adulthood.
Newborn rats (N=26) were randomly assigned to room air (RA) or hyperoxia (85% O2) from postnatal day 1 to 14, then recovered in RA until 1 year of life. Arterial stiffness, renal histomorphometry, and fibrosis in the aorta, heart and kidney was assessed. RNA-sequencing (RNA-seq) of the aorta and kidney was also done.
Neonatal hyperoxia exposure was associated with sustained systemic vascular and cardio-renal alterations at 1 year of age. The rats exposed to hyperoxia had increased aortic and mesenteric artery stiffness as demonstrated by wire and pressure myography. There was glomerulomegaly and tubular injury in rats exposed to neonatal hyperoxia. Hyperoxia exposure altered the transcriptome profile in the aorta and kidney associated with fibrosis and matrix remodeling. Gene set enrichment analysis (Figure) showed that genes most induced in the aorta by hyperoxia were related to “connective tissue development” and “extracellular matrix remodeling”. In the kidney, the genes most downregulated were related to “kidney development” and the antifibrotic bone morphogenic protein (BMP) pathway, while the most upregulated genes included profibrotic pathways such as “extracellular matrix binding”. There was also increased TGF-β1 levels and fibrosis in the aorta, left ventricle and kidney at 1 year.
Neonatal hyperoxia exposure was associated with sustained systemic vascular and cardio-renal alterations in adult rats. Further mechanistic studies to determine how targeted therapies could alter the long-term programming of vascular stiffness and cardio-renal injury after neonatal hyperoxia exposure are indicated.