Impaired transforming growth factor-beta signaling in idiopathic pulmonary arterial hypertension.

Mutations in transforming growth factor-beta family receptor-II, bone morphogenetic protein receptor-2, and activin-like kinase-1 have been associated with pulmonary hypertension. In the present study, we determined that pulmonary arteries in normal lungs and in lungs of patients with emphysema and idiopathic pulmonary arterial hypertension comparably expressed transforming growth factor-beta receptors I and II, Smad(1, 5, 8), Smad2, Smad3, Smad4, phosphorylated Smad(1, 5, 8), and phosphorylated Smad2 (the latter two both indicative of active in vivo signaling) in endothelial cells, as assessed by immunohistochemistry and quantitative morphometry. Medial or intimal smooth muscle cells had weak or absent expression of these molecules. In clear contrast to endothelial cell expression in pulmonary arteries and in endothelial cells lining incipient vessels within plexiform lesions of hypertensive lungs, endothelial cells present in the core of the lesions lacked expression of all examined members of the signaling molecules. These findings were made irrespective of the mutation status of bone morphogenetic protein receptor-2 in hypertensive patients. Our findings suggest that pulmonary artery endothelial cells in both normal and severely hypertensive lungs have active transforming growth factor-beta family signaling, and that loss of signaling might contribute to the abnormal growth of endothelial cells in plexiform lesions in idiopathic pulmonary arterial hypertension.

[1]  N. Voelkel,et al.  The pathobiology of pulmonary hypertension. Endothelium. , 2001, Clinics in chest medicine.

[2]  K. Luo,et al.  Negative feedback regulation of TGF-beta signaling by the SnoN oncoprotein. , 1999, Science.

[3]  O. Volpert,et al.  Smad4/DPC4-mediated tumor suppression through suppression of angiogenesis. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[4]  R. Speich,et al.  Clinical classification of pulmonary hypertension. , 2004, Journal of the American College of Cardiology.

[5]  M. Humbert,et al.  Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. , 2001, The New England journal of medicine.

[6]  J. Campisi,et al.  Ski acts as a co-repressor with Smad2 and Smad3 to regulate the response to type beta transforming growth factor. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[7]  R. Trembath,et al.  Primary Pulmonary Hypertension Is Associated With Reduced Pulmonary Vascular Expression of Type II Bone Morphogenetic Protein Receptor , 2002, Circulation.

[8]  J. Massagué,et al.  Mechanisms of TGF-β Signaling from Cell Membrane to the Nucleus , 2003, Cell.

[9]  R. W. Padgett,et al.  TGF‐β signaling, Smads, and tumor suppressors , 1998 .

[10]  J. Massagué,et al.  Mechanisms of TGF-beta signaling from cell membrane to the nucleus. , 2003, Cell.

[11]  R. Trembath,et al.  Heterozygous germline mutations in BMPR2, encoding a TGF-β receptor, cause familial primary pulmonary hypertension , 2000, Nature Genetics.

[12]  C. Heldin,et al.  Activation of bone morphogenetic protein/Smad signaling in bronchial epithelial cells during airway inflammation. , 2002, American journal of respiratory cell and molecular biology.

[13]  M. Goumans,et al.  Balancing the activation state of the endothelium via two distinct TGF‐β type I receptors , 2002, The EMBO journal.

[14]  R R Markwald,et al.  Embryonic endothelial cells transdifferentiate into mesenchymal cells expressing smooth muscle actins in vivo and in vitro. , 1997, Circulation research.

[15]  M. Frid,et al.  Mature Vascular Endothelium Can Give Rise to Smooth Muscle Cells via Endothelial-Mesenchymal Transdifferentiation: In Vitro Analysis , 2002, Circulation research.

[16]  N. Voelkel,et al.  Severe pulmonary hypertension after the discovery of the familial primary pulmonary hypertension gene. , 2001, The European respiratory journal.

[17]  K. Brown,et al.  Expression of human herpesvirus 8 in primary pulmonary hypertension. , 2003, The New England journal of medicine.

[18]  N. Voelkel,et al.  Microsatellite Instability of Endothelial Cell Growth and Apoptosis Genes Within Plexiform Lesions in Primary Pulmonary Hypertension , 2001, Circulation research.

[19]  J. Massagué,et al.  Controlling TGF-β signaling , 2000, Genes & Development.

[20]  M. Botney.  Vascular Remodeling in Primary Pulmonary Hypertension: What Role for Transforming Growth Factor-Beta? , 1994 .

[21]  S. Hodge,et al.  Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. , 2000, American journal of human genetics.

[22]  J. Loscalzo.  Genetic clues to the cause of primary pulmonary hypertension. , 2001, The New England journal of medicine.

[23]  K. Luo,et al.  Negative Feedback Regulation of TGF-β Signaling by the SnoN Oncoprotein , 1999 .

[24]  M. Humbert,et al.  Pathologic assessment of vasculopathies in pulmonary hypertension. , 2004, Journal of the American College of Cardiology.

[25]  G. Semenza,et al.  Expression of angiogenesis‐related molecules in plexiform lesions in severe pulmonary hypertension: evidence for a process of disordered angiogenesis , 2001, The Journal of pathology.

[26]  P. Thistlethwaite,et al.  Signaling molecules in nonfamilial pulmonary hypertension. , 2003, The New England journal of medicine.

[27]  J. Massagué,et al.  TGFβ Signaling in Growth Control, Cancer, and Heritable Disorders , 2000, Cell.

[28]  Y. Bang,et al.  Rapid induction of p21WAF1 but delayed down-regulation of Cdc25A in the TGF-β-induced cell cycle arrest of gastric carcinoma cells , 1999, British Journal of Cancer.

[29]  R. W. Padgett,et al.  TGF-beta signaling, Smads, and tumor suppressors. , 1998, BioEssays : news and reviews in molecular, cellular and developmental biology.

[30]  J. Massagué,et al.  Controlling TGF-beta signaling. , 2000, Genes & development.

[31]  C. Heldin,et al.  Activation of the TGF-beta/activin-Smad2 pathway during allergic airway inflammation. , 2001, American journal of respiratory cell and molecular biology.

[32]  R. Weinberg,et al.  SnoN and Ski protooncoproteins are rapidly degraded in response to transforming growth factor beta signaling. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[33]  L. Gold,et al.  Vascular remodeling in primary pulmonary hypertension. Potential role for transforming growth factor-beta. , 1994, The American journal of pathology.

[34]  V. Peinado,et al.  Characterization of pulmonary vascular remodelling in smokers and patients with mild COPD , 2002, European Respiratory Journal.

[35]  B. Groves,et al.  Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension. , 1994, The American journal of pathology.

[36]  S. Mandriota,et al.  Transforming Growth Factor 1 Down-regulates Vascular Endothelial Growth Factor Receptor 2/flk-1 Expression in Vascular Endothelial Cells (*) , 1996, The Journal of Biological Chemistry.

[37]  M. Humbert,et al.  Mutations in the Tgfβ Superfamily Receptors, BMPR2 and ALK-1 , Cause Pulmonary Hypertension , 2001 .

[38]  R. L. Williams,et al.  Three-dimensional reconstruction of pulmonary arteries in plexiform pulmonary hypertension using cell-specific markers. Evidence for a dynamic and heterogeneous process of pulmonary endothelial cell growth. , 1999, The American journal of pathology.

[39]  A. Roberts.  The ever-increasing complexity of TGF-β signaling , 2002 .