Signaling molecules in nonfamilial pulmonary hypertension

N Engl J Med. 2003 Feb 6;348(6):500-9. doi: 10.1056/NEJMoa021650.


Background: Biochemical, genetic, and clinical evidence indicates that smooth-muscle proliferation around small pulmonary vessels is an essential part of the pathogenesis of pulmonary hypertension. Mutations in the bone morphogenetic protein receptor type 2 (BMPR2) have been linked to familial cases of pulmonary hypertension, but the molecular basis of the common nonfamilial forms is unknown.

Methods: We evaluated the pattern of expression of angiopoietin-1, a protein involved in the recruitment of smooth-muscle cells around blood vessels; TIE2, the endothelial-specific receptor for angiopoietin-1; and bone morphogenetic protein receptor type 1A (BMPR1A) and BMPR2 in lung-biopsy specimens from patients with pulmonary hypertension and from normotensive control patients. The effect of angiopoietin-1 on the modulation of BMPR expression was also evaluated in subcultures of human pulmonary arteriolar endothelial cells.

Results: The expression of angiopoietin-1 messenger RNA and the protein itself and the phosphorylation of TIE2 were strongly up-regulated in the lungs of patients with various forms of pulmonary hypertension, correlating directly with the severity of disease. A mechanistic link between familial and acquired pulmonary hypertension was demonstrated by the finding that angiopoietin-1 shuts off the expression of BMPR1A, a transmembrane protein required for BMPR2 signaling, in pulmonary arteriolar endothelial cells. Similarly, we found that the expression of BMPR1A was severely reduced in the lungs of patients with various forms of acquired as well as primary nonfamilial pulmonary hypertension.

Conclusions: These findings suggest that all forms of pulmonary hypertension are linked by defects in the signaling pathway involving angiopoietin-1, TIE2, BMPR1A, and BMPR2 and consequently identify specific molecular targets for therapeutic intervention.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Activin Receptors, Type I / biosynthesis*
  • Activin Receptors, Type I / genetics
  • Angiogenesis Inducing Agents / biosynthesis*
  • Angiogenesis Inducing Agents / genetics
  • Angiopoietin-1
  • Bone Morphogenetic Protein Receptors, Type I
  • Bone Morphogenetic Protein Receptors, Type II
  • Gene Expression Regulation*
  • Humans
  • Hypertension, Pulmonary / classification
  • Hypertension, Pulmonary / genetics
  • Hypertension, Pulmonary / metabolism*
  • Lung / metabolism*
  • Lung / pathology
  • Membrane Glycoproteins / biosynthesis*
  • Membrane Glycoproteins / genetics
  • Phosphorylation
  • Protein Serine-Threonine Kinases / biosynthesis*
  • Protein Serine-Threonine Kinases / genetics
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Receptor Protein-Tyrosine Kinases / biosynthesis*
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor, TIE-2
  • Receptors, Growth Factor*
  • Severity of Illness Index
  • Signal Transduction
  • Transcription, Genetic


  • ANGPT1 protein, human
  • Angiogenesis Inducing Agents
  • Angiopoietin-1
  • Membrane Glycoproteins
  • RNA, Messenger
  • Receptors, Growth Factor
  • Receptor Protein-Tyrosine Kinases
  • Receptor, TIE-2
  • Protein Serine-Threonine Kinases
  • Activin Receptors, Type I
  • BMPR1A protein, human
  • BMPR2 protein, human
  • Bone Morphogenetic Protein Receptors, Type I
  • Bone Morphogenetic Protein Receptors, Type II