CV Science

Christophe GUIGNABERT PhD Cardiovascular Research

Course and current status

Christophe GUIGNABERT, PhD, ATSF, FERS joined Inserm in 2009 and is currently Research Director (DR1- Full Professor of Molecular Biology and Physiology) at Université Paris-Saclay (HPPIT, Le Kremlin-Bicêtre, FRANCE). He leads Team 1, “Endothelial Dysfunction and Therapeutic Innovation in Pulmonary Hypertension (PH)”, which focuses on the molecular and cellular mechanisms underlying pulmonary vascular remodeling and the development of innovative therapeutic strategies, with a major emphasis on BMP/TGF-β signaling.

-Since 2017: Full Professor of Molecular Biology & Physiology (DR1) at Université Paris-Saclay / Inserm (HPPIT - UMR 1358) - Team 1

-2012-17: Associate Professor - Chargé de Recherche (CR1 Inserm) - Université Paris-Saclay / Inserm (HPPIT - UMR 999) - Team 1

-2012: Accreditation to Surpervise Research (Habilitation - HDR)                                    

-2010-12:  Assistant Professor (CR2 Inserm) - Université Paris-Saclay / Inserm

-2008-10:  Post-Doc #3: Université Paris-Sud - Humbert's lab

-2006-08:  Post-Doc #2: STANFORD University, CA, USA - Rabinovitch's lab

-2004-06:  Post-Doc #1: UMR_S 651 - Univ. Paris-Est Créteil - Adnot's Lab

-2001-05:  Ph.D "Epithelial Alveolar Repair" - Univ. Paris-Est Créteil - d'Ortho's lab

Scientific summary

As a researcher, my work aims to decipher the molecular and cellular mechanisms driving vascular remodeling in Pulmonary Hypertension (PH), with the ultimate goal of identifying and validating novel therapeutic targets. I specifically investigate how dysfunctions of the BMP/TGF-β family shape endothelial heterogeneity and regulate endothelial-microenvironment interactions in PH.

Over the past 2 decades, our research has significantly advanced the understanding of pulmonary vascular endothelial dysfunction in PAH/PH. We have identified key alterations, including the acquisition and maintenance of a pro-inflammatory phenotype with overexpression of adhesion molecules (E-selectin, ICAM-1, VCAM-1) and excessive cytokine and chemokine secretion (e.g., IL-1α, IL-6, IL-8, IL-12, MIF, and CCL2). In addition, we have demonstrated an overproduction of growth factors such as FGF-2, Ang II, MIF, and activins, which contribute to disease progression.

A major breakthrough from our team was the demonstration that the pulmonary vascular remodeling in PAH/PH is driven by aberrant overactivation of the activin–pSmad2/3 signaling axis. These findings helped establish the activin pathway as a therapeutic target and partly contributed to the rationale for the clinical development of Sotatercept. We were also the first to show that selective loss or inhibition of BMP-9/BMPRII does not predispose to experimental PH; on the contrary, it confers partial protection against disease development. Notably, we provided compelling evidence that combined loss of BMP-9 and BMP-10 induces dilation of the pulmonary capillary bed and a phenotype closely resembling hereditary hemorrhagic telangiectasia (HHT) and hepatopulmonary syndrome (HPS). We further demonstrated increased pericyte coverage in remodeled pulmonary arteries in both experimental and human PH. In addition, our studies revealed that dasatinib induces pulmonary endothelial dysfunction, providing mechanistic insight into dasatinib-associated pleural effusion and its link to increased susceptibility to PAH.

In the search for novel treatments, our preclinical studies have identified promising drug candidates capable of limiting pulmonary vascular remodeling, including finerenone, pirfenidone, sacubitril/valsartan, as well as targeted antagonists of CXCL12 (Patent WO2018011376) and MIF (Patent WO2015173433). Some of these compounds are currently undergoing clinical development.

Finally, our team has recently identified 5 prognostic biomarkers for PAH—CXCL9, TRAIL, ß-NGF, activin A, and FSTL3 (Patents WO2018011376 and WO2015173433)—which can predict patient outcomes. We are now expanding this work to develop and validate biomarker signatures enabling patient stratification, risk prediction, and assessment of treatment responses to support personalized management of PAH.

Scientific Production: Dr. Dr. Guignabert is a highly accomplished researcher with more than 150 original research articles, 50 review articles, and over 15 book chapters. He is also the holder of four patents. He has been invited to speak at numerous national and international conferences and is widely recognized in his field. In addition to his research activities, Dr. Guignabert serves as Associate Editor of the European Respiratory Journal. He is also a dedicated mentor, having supervised multiple MD and PhD trainees, many of whom have gone on to establish successful, independent research careers.

Lab Website: https://www.hppit.fr/team-1