The antiproliferative effects of imatinib are attributed to inhibition of the tyrosine kinase activity of PDGFR [
20]. Beyond that, PDGFR activation is known to enhance the tone of various vessel types from different species by the increase of intracellular Ca
2+ [
26,
71]. So far it is unknown, if imatinib-induced relaxation is linked to PDGFR-inhibition, and further if PDGF also contracts pulmonary vessels. Here, we showed that PDGF-BB contracts PVs and that this contraction is completely prevented by the unselective PDGFR-αβ-inhibitor imatinib. PDGFR-β-inhibition (SU6668) abolished PDGF-BB-induced contraction, whereas PDGFR-α-inhibition (ponatinib) reduced it only mildly and non-significantly. In general, PDGF-BB binds to PDGFR-αα, αβ or ββ [
23]. Hence, our results suggest 1) a leading role of PDGFR-ββ or/and PDGFR-αβ, as inhibition of the β-subunit completely prevented PDGF-BB-induced contraction and 2) a minor role of PDGFR-αα, as inhibition of the α-subunit did not prevent contraction. SU6668 has multiple targets such as Aurora kinases, TBK1 and the RTK VEGFR-2, FGFR-1, EGFR or FLK-1/KDR [
35]. SU6668 (5 μM) blocks VEGFR-2 (IC
50 0.34–2.43 μM) and FGFR-1 (IC
50 1.2–10 μM) only moderately, whereas ponatinib (100 nM) potently blocks VEGFR-2 (IC
50 1.5 nM) and FGFR-1 (IC
50 2.2 nM). Hence, if the inhibition of VEGFR-2 or FGFR-2 would prevent the PDGF-BB-induced contraction, ponatinib should be more effective than SU6668. In addition, the complete inhibition of EGFR (IC
50 >100 nM) or FLK-1/KDR (IC
50 2.1 μM) would require SU6668 concentrations above 5 μM. These considerations support the idea that the contractile effect of PDGF-BB is prevented by inhibition of PDGFR-β [
32‐
37,
72‐
75]. Conversely, the PDGFR-β inhibitors SU6668 and DMPQ relaxed pre-constricted PVs, whereas the PDGFR-α inhibitor ponatinib had no effect. Further, after inhibition of PDGFR-β by SU6668 or DMPQ (both 5 μM), imatinib only relaxed pre-constricted PVs at 100 μM. These data suggests that imatinib-induced relaxation depends on PDGFR-β inhibition. Thus, our findings suggest that PDGFR-β antagonism does not only attenuate the establishment of PH [
10,
76], but also mediates vasorelaxation. Our results are supported by Shiba et al. [
77] who proved in cerebral arteries that imatinib counteracts PDGFR-signaling and prevents vasospasm. In an effort to identify a link between ET-1- and PDGFR signaling, we studied if activated ET-1 receptors interact anyhow with PDGFR. To this end, we inhibited PDGFR prior to the treatment with ET-1. Neither inhibition of PDGFR (imatinib), PDGFR-β (SU6668) nor PDGFR-α (ponatinib) did reduce ET-1-induced contraction. Hence, it appears that stimulation of ET-1 receptors does not activate PDGFR or it takes place, but without being sufficient to mediate contraction, possibly because ligand-binding is missing. Recently, Harada and coworkers [
78] could show in rat L6 myoblasts that stimulation of ET-1 receptors activates PDGFR downstream signaling by an unknown mechanism. However, they did not study ET-1-induced phosphorylation of PDGFR [
78].
Irrespective from a possible interaction of ET-1 and PDGFR, the relaxant effect of imatinib is not limited to ET-1, as it relaxed PAs pre-constricted with U46619 [
14,
15], serotonin [
14] or L-NAME [
15]. Further, imatinib exerts relaxant effects in different tissues, i.e. systemic vessels [
15], prostatic tissue [
58], PAs [
14,
15], corpus cavernosum [
57], myometrium [
79] and stomach [
80] from humans, rabbits, GPs, rats or sheep. Thus, imatinib-induced relaxation appears to be a widespread phenomenon. Beyond that, other TKIs also exert pulmonary vascular relaxant effects (nilotinib/sorafenib) [
14] or prevent experimental pulmonary vascular remodeling by PDGFR-inhibition (nilotinib/dasatinib). Within this context, dasatinib plays a particular role, as it also inhibits Src kinases playing a pivotal role in pulmonary arterial remodeling [
81,
82]. That is probably why; dasatinib reverses experimental PH even more potently than imatinib [
81]. However in patients with CML, dasatinib also provoke drug-induced PAH by an unknown mechanism [
83,
84]. Fortunately, this dasatinib-associated adverse effect appears to be reversible, rare and limited to dasatinib [
85‐
88].