RT Journal Article
SR Electronic
T1 Dual mechanism of platelet-derived growth factor (PDGF)-receptor: Contribution of vascular response to the pathogenesis of pulmonary hypertension (PH)
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP PA2437
DO 10.1183/13993003.congress-2015.PA2437
VO 46
IS suppl 59
A1 Annette D. Rieg
A1 Carolin Anker
A1 Julia Krabbe
A1 Rolf Rossaint
A1 Stefan Uhlig
A1 Christian Martin
YR 2015
UL http://erj.ersjournals.com/content/46/suppl_59/PA2437.abstract
AB Introduction: PDGF and its receptor PDGFR are highly expressed in PH and mediate proliferation. Previously, we showed that PDGF-BB contracts pulmonary vessels which are relaxed by the PDGFR antagonist Imatinib.Aims and objectives: We studied the mechanisms of PDGF-BB-induced contraction and the vascular effects of PDGFR-α/β antagonists in pulmonary veins (PVs) using „precision-cut lung slices“ (PCLS).Methods: PCLS from guinea pigs were prepared as described [1]. In PVs, PDGFR-α/β antagonists were studied after pre-contraction with ET-1 and PDGF-BB-induced contraction was studied after inhibition of several signaling pathways. Changes of the vascular tone, indicated as changes of the vessel cross-sectional area were measured by videomicroscopy. Statistics was performed by a „linear mixed model analysis“ (SAS 9.2).Results: PDGF-BB (100nM) contracted PVs about 70% (p<0.001). Inhibition of PDGFR/PDGFR-β (Imatinib/SU6668), but not inhibition of PDGFR-α (Ponatinib) prevented the contractile effect of PDGF-BB. Vice versa, only Imatinib/SU6668 relaxed PVs. Inhibition of L-Type Ca2+-channels reduced PDGF-BB-induced contraction, whereas inhibition of ROCK/PKC was not significant. Blocking of EP1/3- and TP-receptors inhibited PDGF-BB-induced contraction significantly, whereas inhibition of EP4 only slightly reduced it.Conclusions: PDGFR-β regulates the vascular tone. PDGF-BB-induced contraction is mediated by the increase of intracellular Ca2+ and by the activation of EP1/3/4- and TP-receptors. Further insights in PDGF-BB-signaling may contribute to generate new therapeutics for PH.Literature: 1) Ressmeyer (2006) Eur Respir J 28: 603-11.