Abstract
BackgroundPulmonary hypertension (PH) is a complex pulmonary vascular disease characterized by an imbalance in vasoconstrictor/vasodilator signaling within the pulmonary vasculature. Recent evidence suggests that exposure to hypoxia early in life can cause alterations in the pulmonary vasculature and lead to the development of PH. However, the long-term impact of postnatal hypoxia on lung development and pulmonary function remains unknown. N6-methyladenosine (m6A) regulates gene expression and governs many important biological processes. However, the function of m6A in the development of PH remains poorly characterized. Thus, the purpose of this investigation was to test the two-fold hypothesis that (1) postnatal exposure to hypoxia would alter lung development leading to PH in adult rats, and (2) m6A modification would change in rats exposed to hypoxia, suggesting it plays a role in the development of PH.MethodsTwenty-four male Sprague–Dawley rats were exposed to a hypoxic environment (FiO2: 12%) within 24 h after birth for 2 weeks. PH was defined as an increased right ventricular pressure (RVP) and pathologic changes of pulmonary vasculature measured by α-SMA immunohistochemical staining. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) was performed to analyze m6A modification changes in lung tissue in 2- and 9-week-old rats that were exposed to postnatal hypoxia.ResultsMean pulmonary arterial pressure, lung/body weight ratio, and the Fulton index was significantly greater in rats exposed to hypoxia when compared to control and the difference persisted into adulthood. m6A methyltransferase and demethylase proteins were significantly downregulated in postnatal hypoxia-induced PH. Distinct m6A modification peak-related genes differed between the two groups, and these genes were associated with lung development.ConclusionsOur results indicate postnatal hypoxia can cause PH, which can persist into adulthood. The development and persistence of PH may be because of the continuous low expression of methyltransferase like 3 affecting the m6A level of PH-related genes. Our findings provide new insights into the impact of postnatal hypoxia and the role of m6A in the development of pulmonary vascular pathophysiology.
Highlights
Pulmonary hypertension (PH) is a complex pathology regulated by a multitude of molecular pathways and processes
Postnatal hypoxia dysregulates lung development and leads to PH Lung/body wet weight ratio increased after 2 weeks of exposure to hypoxia, suggesting that pulmonary edema occurred in the hypoxia group
The mean alveolar number (MAN) suggested that the development of alveoli in the hypoxia group was Postnatal hypoxia decreased the expression of m 6A related proteins To further explore m6A methylation after exposure to postnatal hypoxia, we determined the expression of five m6A-related proteins in lung tissue
Summary
Pulmonary hypertension (PH) is a complex pathology regulated by a multitude of molecular pathways and processes. Previous results from our laboratory revealed that embryonic growth is related to PH and pulmonary vascular function, as intrauterine growth retardation (IUGR) resulted in decreased pulmonary vascular growth [1] and extrauterine growth retardation (EUGR) was associated with varying degrees of pulmonary arterial hypertension (PAH) later in life [1, 3] These results suggest that environmental factors in early life play a critical role in developing PH and result in long-term ramifications for pulmonary function. Of note, m6A levels change during organ maturation and early life processes [17,18,19], and several investigations have suggested a temporal progression of m6A modification of different tissues and different stages of life [20, 21] Despite these prospects, the dynamic m6A changes in lung or pulmonary vascular diseases remain to be elucidated. The purpose of this investigation was to test the two-fold hypothesis that (1) postnatal exposure to hypoxia would alter lung development leading to PH in adult rats, and (2) m6A modification would change in rats exposed to hypoxia, suggesting it plays a role in the development of PH
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