Dual mechanism of platelet-derived growth factor (PDGF)-receptor: Contribution of vascular response to the pathogenesis of pulmonary hypertension (PH)

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 2+ -channels reduced PDGF-BB-induced contraction, whereas inhibition of ROCK/PKC was not significant. Blocking of EP 1/3 - and TP-receptors inhibited PDGF-BB-induced contraction significantly, whereas inhibition of EP 4 only slightly reduced it. Conclusions: PDGFR-β regulates the vascular tone. PDGF-BB-induced contraction is mediated by the increase of intracellular Ca 2+ and by the activation of EP 1/3/4 - 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.