Preterm birth interrupts physiological lung development in the saccular phase with immature alveolarisation and compromised vasculogenesis leading to impaired gas exchange [
1]. Thus, extremely preterm babies suffer respiratory distress with the necessity of oxygen supplementation and mechanical respiratory support [
2]. Over the last decades, prenatal prevention and postnatal treatment of respiratory distress have seen many data-driven improvements including antenatal steroids, surfactant application, non-invasive continuous positive airway pressure, and caffeine citrate treatment [
2‐
5]. However, the incidence of long term sequelae affecting alveolar and pulmonary vascular structures is rising. Thus, the chronic lung disease bronchopulmonary dysplasia (BPD) develops in 32 to 59% of children born before 29 weeks of gestational age [
6,
7]. BPD is responsible for longer postnatal hospitalisations, higher frequency of readmissions, and long-term lung function impairment [
8,
9]. Additionally, cardiovascular remodelling with decreased pulmonary capillary density and increased arterial wall thickness contributes to poor outcomes [
10]. Between 23 and 39 percent of patients with a combination of BPD and pulmonary hypertension (BPD-PH) die already within the first year of life [
11‐
13]. Moreover, BPD-PH is associated with prolonged time on the respirator, longer oxygen dependency, higher tracheostomy rates, and higher frequency of readmissions to the intensive care setting compared to BPD alone [
14]. Recently, it has been shown that echocardiographic right ventricular performance markers significantly worsen already on the 7th day of life (DOL) in very preterm infants who will later be diagnosed with BPD [
15].
Endothelin-1 (ET-1) receptor antagonists offer a promising field of research in preterm chronic lung disease [
16,
17]. ET-1 is thought to be related to major features of preterm chronic lung disease such as lung fibrosis, impaired alveolarization, and diminished angiogenesis [
18,
19]. Further, ET-1 increases pulmonary vascular resistance and right ventricular afterload with consecutive right ventricular hypertrophy (RVH) [
20,
21]. Therefore, an intervention at the ET-1 receptor level might have a positive effect on pulmonary vascular resistance and right ventricular remodelling. In 2021, ET-1 receptor antagonists found their way into BPD-PH treatment recommendations for children [
22]. However, the influence of pharmacological ET-1 receptor blockade on cardiovascular remodelling in the context of BPD has neither been examined in human patients nor in animal models. The aim of this study was to prospectively evaluate the potential of the dual ET-1 receptor antagonist (ET
A and ET
B receptor) macitentan to mitigate alveolar and cardiovascular remodelling using the established in-vivo hyperoxia BPD infant rat model [
23‐
25]. We hypothesised that oral administration of macitentan attenuates hyperoxia-induced alveolar rarefaction and enlargement, vascular fibrosis, vascular rarefaction, and right ventricular hypertrophy.