We recently reported that platelet-derived growth factor (PDGF) induces collagen synthesis and proliferation of pulmonary artery smooth muscle cells (PASMCs) via a calpain-initiated intracrine TGFβ1 pathway in pulmonary arterial hypertension. In the present study, we investigated the effect of bone morphogenetic protein (BMP4) on PDGF-induced collagen synthesis in PASMCs. PASMCs were incubated with PDGF-BB (10 ng/ml) in the absence and presence of BMP4 (30 ng/ml) for 30 min to 24 h. Then the protein levels of collagen-I, p-Smad2/3, p-Smad1/5, and intracellular active TGFβ1, and calpain activity were measured. BMP4 induced an increase in p-Smad1/5 but had no effect on the protein levels of collagen-I, p-Smad2/3, and intracrine TGFβ1, and calpain activity in control PASMCs. However, BMP4 attenuated the increases in protein levels of collagen-I, p-Smad2/3, and intracrine TGFβ1, and calpain activity induced by PDGF-BB in PASMCs. Knocking-down of Smad1/5 did not prevent the inhibitory effects of BMP4 on PDGF-BB-induced increases in protein levels of collagen-I, p-Smad2/3, and intracrine TGFβ1, and calpain activity. Further, BMP4 did not affect the cytosolic [Ca2+], p-ERK or p-Src. In contrast, BMP4 increased PKA activity which is an inhibitor of calpain activation. Treatment of PASMCs with myristoylated protein kinase inhibiter (mPKI) prevented the inhibitory effects of BMP4 on PDGF-BB-induced calpain activation. These results demonstrate that BMP4 inhibits PDGF-induced collagen synthesis in PASMCs and that PKA activation induced by BMP4 contributes to the inhibitory effect of BMP4 on calpain-initiated intracrine TGFβ1 pathway. The cross-talk between BMP4 and PDGF signaling pathways may provide novel mechanistic insight into the pathogenesis of pulmonary arterial hypertension.