Altered Growth Responses of Pulmonary Artery Smooth Muscle Cells From Patients With Primary Pulmonary Hypertension to Transforming Growth Factor-β 1 and Bone Morphogenetic Proteins

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Abstract
Background Mutations in the type II receptor for bone morphogenetic protein (BMPR-II), a receptor member of the transforming growth factor-β (TGF-β) superfamily, underlie many cases of familial and sporadic primary pulmonary hypertension (PPH). We postulated that pulmonary artery smooth muscle cells (PASMCs) from patients with PPH might demonstrate abnormal growth responses to TGF-β superfamily members. Methods and Results For studies of 3 H-thymidine incorporation or cell proliferation, PASMCs (passages 4 to 8) were derived from main pulmonary arteries. In control cells, 24-hour incubation with TGF-β 1 (10 ng/mL) or bone morphogenetic protein (BMP)-2, -4, and -7 (100 ng/mL) inhibited basal and serum-stimulated 3 H-thymidine incorporation, and TGF-β 1 and BMPs inhibited the proliferation of serum-stimulated PASMCs. In contrast, TGF-β 1 stimulated 3 H-thymidine incorporation (200%; P 125 I-TGF-β 1 confirmed that the abnormal responses in PPH cells were not due to differences in TGF-β receptor binding. Mutation analysis of PASMC DNA failed to detect mutations in TGF-βRII and Alk-1 but confirmed the presence of a mutation in BMPR-II in 1 of 5 PPH isolates. Conclusions We conclude that PASMCs from patients with PPH exhibit abnormal growth responses to TGF-β 1 and BMPs and that altered integration of TGF-β superfamily growth signals may contribute to the pathogenesis of PPH.