Endothelial dysfunction & Cell miscommunication

Christophe Guignabert

Our research team is dedicated to investigating the mechanisms behind pulmonary arterial hypertension (PAH) and its associated pulmonary endothelial dysfunction. This dysfunction plays a critical role in disease susceptibility and the development of pulmonary vascular remodeling. To gain a better understanding of the pathogenesis of PAH and the role of pulmonary endothelial (dys)function in it, we are focusing on obtaining additional information about the altered phenotype of pulmonary endothelial cells (ECs), their communication with resident vascular cells, and immune cells. Our ultimate goal is to identify novel therapeutic strategies to help patients with PAH.

Our research approach is translational, meaning we aim to translate the results of our basic research into clinical applications to prevent and treat PAH. We have already observed that pulmonary ECs undergo several major functional alterations, including: (1) a shift from a quiescent state with no adhesion capacity to an activated state with high adhesion capacity; (2) a pro-proliferative and apoptosis-resistant aberrant phenotype; (3) a pro-inflammatory phenotype characterized by excessive release of key cytokines and chemokines (including IL-1α, IL-6, IL-8, IL-12, CCL-2, and MIF) and increased expression of adhesion molecules (ICAM-1, VCAM-1, and E-selectin); (4) excessive production and secretion of key growth factors such as serotonin, PDGF, FGF-2, leptin, angiotensin-II (AngII) as well as ligands of TGF-β families, such as activins. Our research has also revealed that loss or selective inhibition of BMP-9 and BMP-10 does not predispose to experimental pulmonary hypertension, but prevents or partially protects against this pathology. In addition, we have identified that exposure to high doses of dasatinib can cause pulmonary vascular toxicity due to exaggerated ROS production, thus increasing susceptibility to the development of PAH and facilitating the appearance of pleural effusions.

However, the underlying mechanisms of PAH remain largely unknown, underscoring the need for more in-depth and integrated research. Therefore, our research team focuses on two main axes:

• Identification of the molecular mechanisms involved in the interactions of pulmonary endothelial cells with their environment, notably studying the importance of BMPR-II/Smad1/5/8 and TGF-β/activins/Smad2/3 signaling pathways in endothelial function and pulmonary vascular remodeling.
• In-depth analysis of the interactions between the endothelium and pericytes as well as immune cells.

We use a variety of research tools for our translational study, ranging from in vitro functional studies of pulmonary ECs, smooth muscle cells, and pericytes obtained from PAH patients and control subjects, to in situ immunohistochemical studies on pulmonary specimens from patients with idiopathic PAH and control subjects without pulmonary vascular disease, as well as preclinical in vivo models to study the initiation and progression of PAH.

Our team is dedicated to developing new therapeutic strategies to improve the altered pulmonary endothelial function in PAH, specifically targeting the molecular mechanisms involved in pulmonary endothelial (dys)function and pulmonary vascular remodeling. We are confident that this research can help identify new treatments to assist patients with PAH. This hypothesis guides our research work, which is supported by funding from the Fondation pour la Recherche Médicale (FRM) (projet Equipe FRM), the french Agence Nationale de la Recherche (ANR) (ANR-16-CE17-0014 'TAMIRAH', ANR franco-allemande DFG 2022 "PHASM », ANR 18-RHUS-0006 DESTINATION 2024), the Fondation du Souffle and several industrial contracts.