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1 Department of Medicine, University of Cambridge, Cambridge, Cambridgeshire, United Kingdom
2 Deivision of Medical Genetics, University of Leicester, Leicester, Leicestershire, United Kingdom
* To whom correspondence should be addressed. E-mail: nmw23{at}cam.ac.uk.
Fibroblast proliferation, differentiation and migration contribute to the characteristic pulmonary vascular remodeling seen in primary pulmonary hypertension (PPH). The identification of mutations in the bone morphogenetic protein type II (BMPRII) receptor in PPH have led us to question what role BMPRII and its ligands play in pulmonary vascular remodeling. Thus to further understand the functional significance of BMPRII in the pulmonary vasculature we examined the expression of TGF
superfamily receptors in human lung fibroblasts (HFL) and investigated the role of BMP4 on cell cycle regulation, fibroblast proliferation and differentiation. Furthermore, the signalling pathways involved in these processes were examined. HFLs expressed BMPRI and II mRNA and demonstrated specific I125-BMP4 binding sites. BMP4 inhibited 3H-thymidine incorporation and proliferation of HFLs; protein expression was increased for the cell cycle inhibitor, p21 and reduced for the
positive regulators, cyclin D and cdk2 by BMP4. BMP4 induced differentiation of HFLs into a smooth muscle cell phenotype since protein expression of 
-smooth muscle actin and smooth muscle myosin was increased. Furthermore, p38MAPK, ERK1/2, JNK and Smad1 were phosphorylated by BMP4. Using specific MAPK inhibitors, a dominant negative Smad1 construct and Smad1 siRNA we found that the anti-proliferative and prodifferentiation effects of BMP4 were Smad1 dependent with JNK also contributing to differentiation. Since failure of Smad phosphorylation is a major feature of BMPR2
mutations these results imply that BMPRII mutations may promote the expansion of fibroblasts resistant to the anti-proliferative, pro-differentiation effects of BMPs and suggests a mechanism for the vascular obliteration seen in familial PPH.
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