Pulmonary arterial hypertension (PAH) is a rare (ORPHA: 182090) and aggressive disease with a poor prognosis caused by functional and structural changes in the smaller pulmonary arterioles. Its prevalence ranges between 1 and 9 cases per 100,000 inhabitants with a high rate of morbidity and mortality. Although the development of specific treatments has markedly improved the prognosis, none is sufficiently effective or capable of curing the disease. The search for new targets and therapeutic strategies able of combating PAH in a holistic, multifactorial and precise way is of vital importance to improve the prognosis and quality of life of patients. Both the European Cardiology and Respiratory Societies (ERS and ESC) recently highlighted some specific aspects of endothelial dysfunction, such as the complex role of the pulmonary endothelium in directing the host response in pulmonary and cardiovascular diseases, and its potential value as a target for innovative therapies. The general hypothesis of the ADRENALIN project is that the pulmonary vascular endothelium, being the most important barrier between the circulation and the respiratory system, plays an essential role in the control of health and disease. Consequently, endothelial dysfunction would be a key element to take into account to understand the initiation, development and response to therapies in PAH. Therefore, a better understanding of endothelial damage could make all the difference in the management of such a devastating disease. To date, there is a lack of therapies to effectively address all the pathological signs of the disease. For this ambitious endeavour, we will use a variety of approaches ranging from genetically engineered mice to biomarker analysis in human subjects. Based on strong preliminary results, the ADRENALIN project aims to evaluate the potential use of beta3 adrenergic receptor agonists as a possible therapeutic strategy to protect the endothelium of the pulmonary vasculature from a pre-clinical, molecular and translational approach. In turn, we will explore the role of the axis beta3-adrenergic, mitochondrial dysfunction, cellular metabolism and autophagy in animal models of PAH, and we will study potential nutritional therapeutic strategies. Furthermore, we propose to investigate the intercellular communication between endothelial cells and smooth muscle cells, and its relevance for the development of PAH, considering that a damaged endothelium will be the starting point of pulmonary vascular disease. Finally, with ADRENALIN we will study the potential use of endothelial damage markers to establish a precision medicine strategy in PAH thanks to a better classification of patients based on the degree of endothelial damage.


Grant PID2021-123167OB-I00 funded by MCIN/AEI/ 10.13039/501100011033 and by “ERDF A way of making Europe”

PI: Eduardo Oliver (2022-2025); 199,650 €