Increased pericyte coverage mediated by endothelial-derived fibroblast growth factor-2 and interleukin-6 is a source of smooth muscle-like cells in pulmonary hypertension.
BACKGROUND
Pericytes and their crosstalk with endothelial cells 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-2 and interleukin-6 signaling, leads to abnormal microvascular pericyte coverage causing pulmonary arterial medial thickening.


RESULTS
In human lung tissues, numbers of pericytes are substantially increased (up to 2-fold) in distal PAH pulmonary arteries compared with controls. Interestingly, human pulmonary pericytes exhibit, in vitro, an accentuated proliferative and migratory response to conditioned media from human idiopathic PAH endothelial cells compared with conditioned media from control cells. Importantly, by using an anti-fibroblast growth factor-2 neutralizing antibody, we attenuated these proliferative and migratory responses, whereas by using an anti-interleukin-6 neutralizing antibody, we decreased the migratory response without affecting the proliferative response. Furthermore, in our murine retinal angiogenesis model, both fibroblast growth factor-2 and interleukin-6 administration increased pericyte coverage. Finally, using idiopathic PAH 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-β, in contrast to fibroblast growth factor-2 and interleukin-6, promotes human pulmonary pericyte differentiation into contractile smooth muscle-like cells.


CONCLUSIONS
To the best of our knowledge, this is the first report of excessive pericyte coverage in distal pulmonary arteries in human PAH. We also show that this phenomenon is directly linked with pulmonary endothelial dysfunction.
National Institute of Health and Medical Research, Unit 999, LabEx Laboratory of Excellence in Research on Medication and Innovative Therapeutics, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France (N.R., L.T., M.L.H., A.H., C.P., R.T., C.S., E.F., A.S., D.M., P.D., M.H., C.G.); University Paris-Sud, School of Medicine, Kremlin-Bicêtre, France (N.R., L.T., M.L.H., A.H., C.P., R.T., C.S., E.F., A.S., D.M., P.D., M.H., C.G.); and Public Hospitals of Paris, Pneumology Service, Reference Center of Severe Pulmonary Hypertension, University Hospital Department Thorax Innovation, Hôpital de Bicêtre, Kremlin-Bicêtre, France (A.H., C.S., A.S., D.M., M.H.).
Nicolas
N
Ricard
Ly
L
Tu
Morane
M
Le Hiress
Alice
A
Huertas
Carole
C
Phan
Raphaël
R
Thuillet
Caroline
C
Sattler
Elie
E
Fadel
Andrei
A
Seferian
David
D
Montani
Peter
P
Dorfmüller
Marc
M
Humbert
Christophe
C
Guignabert
D000328:Adult; D000818:Animals; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000473:pathology* / Q000503:physiopathology; D015850:Interleukin-6 / Q000494:pharmacology / Q000502:physiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008833:Microcirculation / Q000502:physiology; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D018919:Neovascularization, Physiologic / Q000502:physiology; D020286:Pericytes / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D011652:Pulmonary Circulation / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D012171:Retinal Vessels / Q000166:cytology / Q000502:physiology
C508600:IL6 protein, human; D015850:Interleukin-6; D016222:Fibroblast Growth Factor 2
cell communication; endothelilal cells; fibroblast growth factor 2; interleukin-6; pericytes; pulmonary arterial hypertension; transforming growth factor beta