Increased Pericyte Coverage Mediated by Endothelial Derived FGF-2 and IL-6 is a Source of Smooth Muscle-Like Cells in Pulmonary Hypertension.
Ricard N, Tu L, Le Hiress M, Huertas A, Phan C, Thuillet R, Sattler C, Seferian A, Fadel E, Montani D, Dorfmüller P, Humbert M, Guignabert C.
INSERM UMR_S 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson & University Paris-Sud, School of Medicine, Kremlin-Bicêtre, France.
BACKGROUND: Pericytes and their crosstalk with endothelial cells (ECs) are critical for the development of a functional microvasculature and vascular remodeling. It is also known that pulmonary endothelial dysfunction is intertwined with the initiation and progression of pulmonary arterial hypertension (PAH). We hypothesized that pulmonary endothelial dysfunction, characterized by abnormal fibroblast growth factor (FGF)-2 and interleukin (IL)-6 signaling, leads to abnormal microvascular pericyte coverage causing pulmonary arterial medial thickening.
METHODS AND RESULTS: In human lung tissues, numbers of pericytes are substantially increased (up to 2-fold) in distal PAH pulmonary arteries as compared to controls. Interestingly, human pulmonary pericytes exhibit, in vitro, an accentuated proliferative and migratory response to conditioned media from human idiopathic PAH (iPAH) ECs as compared to conditioned media from control cells. Importantly, by using an anti-FGF-2 neutralizing antibody, we attenuated these proliferative and migratory responses, whereas by using an anti-IL-6 neutralizing antibody, we decreased the migratory response without affecting the proliferative response. Furthermore, in our murine retinal angiogenesis model, both FGF-2 and IL-6 administration increased pericyte coverage. Finally, using iPAH human and NG2DsRedBAC mouse lung tissues, we demonstrated that this increased pericyte coverage contributes to pulmonary vascular remodeling as a source of smooth muscle-like cells. Furthermore, we found that transforming growth factor (TGF)-β, in contrast to FGF-2 and IL-6, promotes human pulmonary pericyte differentiation into contractile smooth muscle-like cells.
CONCLUSIONS: This is the first report of excessive pericyte coverage in distal pulmonary arteries in human PAH. We are also showing that this phenomenon is directly linked with pulmonary endothelial dysfunction.