Endothelial dysfunction & Cell miscommunication
Christophe Guignabert and Alice Huertas
Our group has already been able to highlight several events reflecting major functional alterations in the pulmonary vascular endothelium, including among others: 1) a transition from a quiescent state (without adhesion capacity) to an activated state with adhesive capacity (Le Hiress et al. Am J Respir Crit Care Med 2015); 2) an aberrant pro-proliferative and apoptosis resistant phenotype (Tu et al. Am J Respir Cell Mol Biol. 2011); 3) a pro-inflammatory phenotype characterized by an excessive release of various key cytokines and chemokines: interleukin (IL)-1α, IL-6, IL-8, IL-12, CCL2/monocyte chemotactic protein (MCP)-1 (Ricard et al. Circulation 2014 ; Le Hiress et al. Am J Respir Crit Care Med 2015); 4) an excessive production and secretion of various key growth factors including fibroblast growth factor-2 (FGF-2; basic FGF) (Tu et al. Am J Respir Cell Mol Biol. 2011; Tu et al. Am J Respir Crit Care Med 2012 ; Ricard et al. Circulation 2014), angiotensin-II (Ang II) (de Man et al. Am J Respir Crit Care. Med 2012), and leptin (Huertas et al. Eur Respir J. 2012 ; Huertas, et al. Eur Respir J. 2015 ; Huertas et al. Chest 2016).
The underlying mechanisms remain unknown and substantial work remains to be done. Our research interests focus on the mechanisms by which pulmonary ECs interact with their environment. Firstly, we are studying the importance of the endothelial BMP9/BMP10 signaling pathway in endothelial (dys)function and vascular remodeling (ANR-17-CE14-0006 'B9inPAH'). Using 3 different approaches of suppressing BMP9 action in rodents, we provided evidence that the selective loss or inhibition of BMP9 does not predispose, but partially prevent or protect against experimental PH (Tu et al. Circ Res. 2019). Secondly, we are exploring in details the endothelium/pericyte interactions as well as the endothelial/immune cell interactions (regulatory T cells (Tregs)) (Equipe FRM label 2015 from the Fondation Recherche Médicale, ANR-15-CE14-0020 'PAHVAP' and ANR-17-CE14-0011 'CoVeR'). Finally, we are studying the iatrogenic mechanisms of certain drugs (project ANSM 'VIGIAPATH'). In particular, we demonstrated that dasatinib causes pulmonary vascular damage through mitochondrial ROS production in a dose-dependent manner, leading to increased susceptibility to develop PAH (Guignabert et al. J Clin Invest. 2016).
To probe these questions in novel ways, our research group has developed a repertoire of unique tools: in vitro studies of cells, including pulmonary ECs, smooth muscle cells and pericytes, from patients with PAH and from controls; in situ immunohistochemical studies in lung specimens from patients with iPAH and controls without pulmonary vascular disease; in vivo models of PH (monocrotaline, chronic hypoxia and SUGEN 5416/chronic hypoxia).
WORKING HYPOTHESIS: A restitution of the aberrant pulmonary endothelial phenotype could stop the progression and/or regress the pulmonary arterial remodeling associated with pulmonary hypertension.
(1) Provide a better understanding of the role played by ECs in pulmonary vascular remodeling
(2) Investigate abnormalities in EC communications with other vascular cells (smooth muscle cells, myofibroblasts and pericytes) and immune cells (Treg)