Endothelial dysfunction in chronic thromboembolic pulmonary hypertension: a comprehensive study of molecular, functional, and metabolic alterations

ENG- This thesis investigates the study of endothelial cells from patients with CTEPH to better understand how and why these cells lose their normal function, contributing to the maintenance of vascular obstruction and disease progression. Through the analysis of their structural, functional, genetic, and metabolic characteristics, this work aims to shed new light on the cellular mechanisms that differentiate CTEPH from other forms of pulmonary hypertension and to open new avenues towards more specific and effective treatments. The study has uncovered various cellular and molecular mechanisms that help to better understand the pathology of CTEPH. It has been observed that endothelial cells from CTEPH patients present alterations in their internal structure—the cytoskeleton—which cause the loss of essential functions such as movement, repair, and response to blood flow. This dysfunction contributes to endothelial malfunction and disease progression. Moreover, it has been detected that this dysfunction affects not only the endothelial cells near the thrombotic tissue but also the circulating endothelial cells in the blood, indicating a systemic rather than only local alteration. This dysfunction has also been studied at the genetic and metabolomic levels, revealing that endothelial cells from CTEPH patients show changes compared to cells from healthy individuals. Particularly notable are alterations in ribosomes (involved in protein production) and mitochondria (the cell’s energy producers), suggesting a profound disruption of cellular function. Likewise, metabolomic analysis reveals significant differences in CTEPH patients, with observed lipid imbalances and reduced fat metabolism. These alterations could help in identifying the disease and guiding future treatments. These findings allow differentiation of CTEPH from other forms of pulmonary hypertension and offer clues to develop more precise diagnostics and targeted therapies that address endothelial dysfunction at its origin