Altered vasoreactivity in neonatal rats with pulmonary hypertension associated with bronchopulmonary dysplasia: Implication of both eNOS phosphorylation and calcium signaling

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.

Interleukin-1 Receptor Antagonist Protects Newborn Mice Against Pulmonary Hypertension

“…Consistent with these findings, the abundance of ET A receptors that mediate the effects of ET-1 on vascular tone was not altered, and α-SMA, a marker of remodeling of the pulmonary arteries associated with increased constriction, was not elevated. Other studies have shown that isolated pulmonary arteries from BPD rats exhibit increased vasoreactivity to U46619 (81) and in a 14 day BPD rat model increased vasoconstriction was associated with PH (82). It is possible that the absence of an increase in arterial α-SMA in hyperoxic pulmonary arteries in our mouse model could explain these discrepancies.…”

Serotonin 2A receptor inhibition protects against the development of pulmonary hypertension and pulmonary vascular remodeling in neonatal mice

“…We (15) previously demonstrated that 5-HT is a potent vasoconstrictor in the developing lung. Recent studies reveal that intrapulmonary arteries isolated from rats with experimental PH/BPD demonstrate increased contractile response to 5-HT (19). Furthermore, pharmacological inhibition of 5-HT 2A-R activation decreases pulmonary vascular resistance in fetal sheep with experimental PH and protects against the development of experimental PH in mature rodents (16,29).…”

Altered Right Ventricular Mechanical Properties Are Afterload Dependent in a Rodent Model of Bronchopulmonary Dysplasia

“…The development of overt pulmonary hypertension (PH) results in increased afterload to the right ventricle (RV), leading to RV hypertrophy (RVH) and ultimately failure, with high infant morbidity and mortality (Bhat et al, 2012 ). Rodent models of BPD, characterized by postnatal hyperoxia exposure, recapitulate many of the findings of human disease, including arrested alveolar and vascular development, PH and RV dysfunction (Goss et al, 2015 , 2017 ; Dumas de la Roque et al, 2017 ; Liang et al, 2017 ).…”