PDGF may contribute to pulmonary vascular remodeling via several mechanisms. First, PDGF is a potent mitogen, causing increased PASMC proliferation, mainly by the activation of extracellular signal-related kinase 1/2 pathway.40 Interestingly extracellular signal-related kinase 1/2 activation can exert an inhibitory effect on Smad 1/5 signaling, thus compounding the defects due to the loss of BMPR-II. In addition, PDGF increases cell migration and extracellular matrix deposition by inducing the expression of metallomatrix proteases, particularly matrix metalloproteinase 1, 3, and 9. PDGF also potently inhibits apoptosis in vascular smooth muscle cells through the phosphatidylinositol 3 kinase (or PI3K)/Akt pathway.41 Furthermore, TGF-β is recognized to increase the expression of PDGF isoforms, particularly in scleroderma. Imatinib, a tyrosine kinase inhibitor licensed for the treatment of chronic myeloid leukemia, has been investigated42–44 as a possible therapy for PAH. Imatinib is a small molecular inhibitor that targets the adenosine triphosphate binding site of tyrosine kinases, thus blocking the actions of PDGF receptors as well as other kinases. Schermuly et al42 used the monocrotaline rat model and a mouse hypoxic model to demonstrate that animals treated with imatinib had significantly reduced pulmonary artery pressures, higher cardiac index, increased arterial oxygenation, and improved survival when compared to sham-treated animals. The inhibition of PASMC proliferation was observed in the imatinib-treated groups. A single clinical case study43 in a patient with familial PAH showed dramatic improvements after imatinib therapy in 6-min walk distance as well as in a reduction in pulmonary vascular resistance. Two further successful cases44 of longer term treatment have since been reported. A multicenter randomized trial of imatinib therapy is due to report later this year.