Abstract
Bronchopulmonary dysplasia (BPD) consists of an arrest of pulmonary vascular and alveolar growth, with persistent hypoplasia of the pulmonary microvasculature and alveolar simplification. In 25 to 40% of the cases, BPD is complicated by pulmonary hypertension (BPD-PH) that significantly increases the risk of morbidity. In vivo studies suggest that increased pulmonary vascular tone could contribute to late PH in BPD. Nevertheless, an alteration in vasoreactivity as well as the mechanisms involved remain to be confirmed. The purpose of this study was thus to assess changes in pulmonary vascular reactivity in a murine model of BPD-PH. Newborn Wistar rats were exposed to either room air (normoxia) or 90% O2 (hyperoxia) for 14 days. Exposure to hyperoxia induced the well-known features of BPD-PH such as elevated right ventricular systolic pressure, right ventricular hypertrophy, pulmonary vascular remodeling and decreased pulmonary vascular density. Intrapulmonary arteries from hyperoxic pups showed decreased endothelium-dependent relaxation to acetylcholine without any alteration of relaxation to the NO-donor sodium nitroprusside. This functional alteration was associated with a decrease of lung eNOS phosphorylation at the Ser1177 activating site. In pups exposed to hyperoxia, serotonin and phenylephrine induced exacerbated contractile responses of intrapulmonary arteries as well as intracellular calcium response in pulmonary arterial smooth muscle cells (PASMC). Moreover, the amplitude of the store-operated Ca2+ entry (SOCE), induced by store depletion using a SERCA inhibitor, was significantly greater in PASMC from hyperoxic pups. Altogether, hyperoxia-induced BPD-PH alters the pulmonary arterial reactivity, with effects on both endothelial and smooth muscle functions. Reduced activating eNOS phosphorylation and enhanced Ca2+ signaling likely account for alterations of pulmonary arterial reactivity.
Highlights
Preterm birth causes infants to be born while the lung is still immature and unable to maintain adequate gas exchange [1]
Immunostaining of von Willebrand factor (vWF) showed that neonatal hyperoxia significantly decreased pulmonary vascular density (Fig 1E and 1F)
Altered vascular tone contributes to the pathophysiology of bronchopulmonary dysplasia (BPD)-pulmonary hypertension (PH), vasoreactivity has been poorly examined in this disease
Summary
Preterm birth causes infants to be born while the lung is still immature and unable to maintain adequate gas exchange [1]. Preterm infants often require respiratory support including assisted ventilation and supplemental oxygen therapy. These life-saving interventions can induce complications, among which bronchopulmonary dysplasia (BPD) is one of the most serious. BPD consists more prominently of an arrest of pulmonary vascular and alveolar growth, with persistent hypoplasia of the pulmonary microvasculature and alveolar simplification [2]. A dysmorphic growth and an impaired function of the pulmonary vasculature can result in pulmonary hypertension (PH) and subsequently lead to right ventricular hypertrophy, in 25 to 40% of the cases of BPD [2,3]. PH severely increases morbidity of BPD and, since the underlying pathophysiology is poorly understood, there is no definitive treatment to prevent BPD associated PH (BPD-PH)
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