Chronic thromboembolic pulmonary hypertension (CTEPH) is a major cause of severe pulmonary hypertension (PH) with significant morbidity and mortality. CTEPH is characterised by the presence of organised intraluminal thrombi that cause obliteration of the pulmonary arteries. Surgical removal of thromboembolic material (PEA) is the treatment of choice in these patients. For inoperable patients or those with persistent/recurrent PH, Riociguat is the only approved drug.

Endothelial cells (EC) play a central role in the pathogenesis of PH. This study hypothesises that endothelial dysfunction (ED) is a major factor in the onset and progression of CTEPH, acting by unbalancing vascular homeostasis and predisposing to thrombus stabilisation and an increase in PH. Little is known about the pathogenesis of CTEPH, the mechanisms that lead to the failure to resolve the thrombus and the development of peripheral vascular disease.

In this project we propose four innovative actions:

1. Molecular and metabolic characterisation of ECs derived from patients with CTEPH.
2. To identify a pattern of ED biomarkers in samples before and after administration of Riociguat, PEA or pulmonary angioplasty.
3. To find new therapeutic targets to prevent and treat this endothelial dysfunction.
4. To generate an in vivo model for the study of endothelial pathology in CTEPH.

This proposal has a clear translational focus and goes beyond the state of the art of CTEPH. A better understanding of the pathophysiological mechanisms of SCD derived from these patients will uncover new criteria in the understanding of CTEPH, identify new biomarkers and identify new therapeutic strategies to improve the quality of life of patients and our society.

Understanding the molecular involvement of endothelial dysfunction in CTEPH represents a step forward in finding new biomarkers and therapeutic targets, improving the management of the disease and the life expectancy of patients suffering from it. Increasing the possibilities of developing effective strategies for personalised treatment.

The identification of new biomarkers is of potential commercial interest to pharmaceutical and diagnostic companies. Pharmacological compounds are generally not tested to determine their efficacy in real trials until much later and, very often, not in human diseases until phase II clinical trials. The generation of endothelial cells derived from CTEPH patients and an in vivo model of CTEPH endothelial pathology will provide the means to model the disease in vitro and in vivo. Furthermore, the in vivo model of CTEPH endothelial disease may be patentable.