High levels of placenta growth factor in sickle cell disease promote pulmonary hypertension

Blood. 2010 Jul 8;116(1):109-12. doi: 10.1182/blood-2009-09-244830. Epub 2010 Mar 24.


Pulmonary hypertension is associated with reduced nitric oxide bioavailability and early mortality in sickle cell disease (SCD). We previously demonstrated that placenta growth factor (PlGF), an angiogenic factor produced by erythroid cells, induces hypoxia-independent expression of the pulmonary vasoconstrictor endothelin-1 in pulmonary endothelial cells. Using a lentivirus vector, we simulated erythroid expression of PlGF in normal mice up to the levels seen in sickle mice. Consequently, endothelin-1 production increased, right ventricle pressures increased, and right ventricle hypertrophy and pulmonary changes occurred in the mice within 8 weeks. These findings were corroborated in 123 patients with SCD, in whom plasma PlGF levels were significantly associated with anemia, endothelin-1, and tricuspid regurgitant velocity; the latter is reflective of peak pulmonary artery pressure. These results illuminate a novel mechanistic pathway linking hemolysis and erythroid hyperplasia to increased PlGF, endothelin-1, and pulmonary hypertension in SCD, and suggest that strategies that block PlGF signaling may be therapeutically beneficial.

Trial registration: ClinicalTrials.gov NCT00011648.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Adult
  • Anemia, Sickle Cell / blood*
  • Anemia, Sickle Cell / complications
  • Anemia, Sickle Cell / genetics
  • Animals
  • Cell Line
  • Endothelin-1 / blood*
  • Enzyme-Linked Immunosorbent Assay
  • Humans
  • Hypertension, Pulmonary / blood*
  • Hypertension, Pulmonary / complications
  • Hypertrophy, Left Ventricular / blood
  • Hypertrophy, Left Ventricular / complications
  • Hypertrophy, Left Ventricular / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Myocardium / metabolism
  • Myocardium / pathology
  • Placenta Growth Factor
  • Pregnancy Proteins / blood*


  • Endothelin-1
  • PGF protein, human
  • Pgf protein, mouse
  • Pregnancy Proteins
  • Placenta Growth Factor

Associated data

  • ClinicalTrials.gov/NCT00011648