Affiliation:
1. From the Department of Medicine (N.W.M., X.Y., P.D.U., K.B.J., N.M., K.K.S.), University of Cambridge, Addenbrooke’s and Papworth Hospitals, Cambridge, United Kingdom; and Division of Clinical Genetics (R.C.T.), University of Leicester, Leicester, United Kingdom.
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
<0.001) and cell proliferation in PASMCs from PPH but not from patients with secondary pulmonary hypertension. In addition, BMPs failed to suppress DNA synthesis and proliferation in PASMCs from PPH patients. Reverse transcription–polymerase chain reaction of PASMC mRNA detected transcripts for type I (TGF-βRI, Alk-1, ActRI, and BMPRIB) and type II (TGF-βRII, BMPR-II, ActRII, ActRIIB) receptors. Receptor binding and cross-linking studies with
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.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Physiology (medical),Cardiology and Cardiovascular Medicine
Cited by
397 articles.
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