CV Science

Christophe GUIGNABERT PhD Cardiovascular Research

Course and current status

Christophe GUIGNABERT (PhD, ATSF, FERS) joined Inserm in 2009 and has since been appointed as Director of Research (DR1) - Full Professor of Molecular Biology & Physiology - at UMR_S 999. This is a mixed Inserm-Université Paris-Saclay research unit located within the Paris-Saclay School of Medicine in Le Kremlin-Bicêtre, France.  Since 2010, he is the Director of the Research Team « Endothelial dysfunction & Therapeutic innovation in PAH »

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

-2012-2017: Associate Professor - Chargé de Recherche (CR1 Inserm) - Université Paris-Saclay / Inserm

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

-2010-2012:  Assistant Professor (Chargé de Recherche (CR2 Inserm) - Université Paris-Saclay / Inserm

-2008-2010:  Post-Doct #3: Université Paris-Sud - Humbert's lab

-2006-2008:  Post-Doct #2: STANFORD University, CA, USA - Rabinovitch's lab

-2004-2006:  Post-Doct #1: UMR_S 651 - Univ. Paris-Est Créteil - Adnot's Lab

-2001-2005:  Ph.D "Epithelial Alveolar Repair" - Univ. Paris-Est Créteil - d'Ortho's lab

Scientific summary

As a researcher, my work focuses on deciphering the molecular and cellular mechanisms underlying vascular remodeling in Pulmonary arterial Hypertension (PAH), with the ultimate goal of identifying and validating novel therapeutic targets. Specifically, I investigate how dysfunction in the BMP/TGF-β superfamily contributes to the phenotypic heterogeneity of the pulmonary endothelium and how endothelial cells interact with their microenvironment in the context of PAH/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 pulmonary vascular remodeling in PAH/PH is driven by dysregulation of the BMP/TGF-β pathway, with overactivation of the TGFß-activin-nodal branch. We were the first to show that the selective loss or inhibition of BMP9/BMPRII does not predispose to experimental PH; on the contrary, it confers protection against PH. Notably, we provided clear evidence that the loss of BMP-10, either alone or in combination with BMP-9, induces a phenotype resembling what is observed in hereditary hemorrhagic telangiectasia (HHT) and hepatopulmonary syndrome (HPS). We also provided the first evidence that pericyte coverage is increased in remodeled pulmonary arteries in both experimental and human PH. Furthermore, our studies revealed that dasatinib induces pulmonary endothelial dysfunction, shedding light on dasatinib-related pleural effusion and its association with increased PAH susceptibility.

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, and targeted antagonists of CXCL12 (Patent WO2018011376) and of MIF (Patent WO2015173433). Some of these compounds are currently undergoing clinical development.

Finally, our team has recently discovered 5 prognostic biomarkers for PAH—CXCL9, TRAIL, ß-NGF, activin A, and FSTL3 (Patents WO2018011376 and WO2015173433)—which can predict patient outcomes. This breakthrough has significant implications for both diagnosis and treatment, and we are actively working to further validate these biomarkers in future studies.

Scientific Production: Dr. Guignabert is a highly accomplished researcher with over 150 original research papers, 50 review articles, and more than 15 book chapters to his name. He is also the holder of 4 patents. Dr. Guignabert has been invited to speak at numerous national and international conferences and is highly regarded in his field. In addition to his research, Dr. Guignabert serves as an Associate Editor of the European Respiratory Journal. He is also a dedicated mentor and has guided multiple MD and Ph.D scientists, many of whom have gone on to have productive and well-funded independent careers.

Scientific Focus: Pulmonary hypertension – Vascular remodeling – Endothelial dysfunction – BMP/TGFß – Growth factors – Preclinical models.

Website: http://www.u999.universite-paris-saclay.fr/en/team-1/pah-physiology-topics.html