Treprostinil inhibits the recruitment of bone marrow-derived circulating fibrocytes in chronic hypoxic pulmonary hypertension.
A unique subpopulation of peripheral blood mononuclear cells that exhibit a parallel expression of haematopoietic and mesenchymal markers has been described as "circulating fibrocytes". These cells were demonstrated to obtain a fibroblastic phenotype in tissues or cell culture and contribute to pulmonary fibrotic disorders and tissue remodelling processes. The aim of our study was to characterise the recruitment of circulating fibrocytes in vivo in the model of chronic hypoxic pulmonary hypertension in mice and to analyse the therapeutic effect of the stable prostacyclin analogue trepostinil with respect to this cell population. To track circulating fibrocytes in vivo, we transplanted wild-type mice with bone marrow from ubiquitously eGFP expressing mice and subjected them to chronic hypoxia. We observed significantly increased recruitment of circulating fibrocytes to the remodelled pulmonary resistance arteries in response to hypoxia. Treatment with treprostinil significantly reduced the recruitment of these cells compared to normoxic mice. Treprostinil also reduced right ventricular systolic pressure and slightly reduced the vascular remodelling but failed to reverse the right ventricular hypertrophy. In summary, we show that circulating fibrocytes contribute to hypoxic pulmonary vascular remodelling and may be specifically targeted by a prostacyclin analogue. Further investigations of cellular and paracrine mechanisms are warranted to decipher their role in pulmonary hypertension.
Dept of Lung Development and Remodelling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
V S
VS
Nikam
R T
RT
Schermuly
R
R
Dumitrascu
N
N
Weissmann
G
G
Kwapiszewska
N
N
Morrell
W
W
Klepetko
L
L
Fink
W
W
Seeger
R
R
Voswinckel
D000818:Animals; D000959:Antihypertensive Agents / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use*; D001775:Blood Circulation; D001808:Blood Vessels / Q000187:drug effects / Q000503:physiopathology; D001854:Bone Marrow Cells / Q000187:drug effects; D046528:Chimerism; D002908:Chronic Disease; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D005347:Fibroblasts / Q000187:drug effects*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000188:drug therapy / Q000503:physiopathology; D000860:Hypoxia / Q000503:physiopathology; D007963:Leukocytes, Mononuclear / Q000187:drug effects*; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000503:physiopathology; D011651:Pulmonary Artery / Q000187:drug effects / Q000503:physiopathology
D000959:Antihypertensive Agents; D011464:Epoprostenol; C427248:treprostinil