TY - JOUR
T1 - High levels of placenta growth factor in sickle cell disease promote pulmonary hypertension
AU - Sundaram, Nambirajan
AU - Tailor, Anitaben
AU - Mendelsohn, Laurel
AU - Wansapura, Janaka
AU - Wang, Xunde
AU - Higashimoto, Tomoyasu
AU - Pauciulo, Michael W.
AU - Gottliebson, William
AU - Kalra, Vijay K.
AU - Nichols, William C.
AU - Kato, Gregory J.
AU - Malik, Punam
PY - 2010/7/8
Y1 - 2010/7/8
N2 - 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, inwhom 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. This trial was registered at http://clinicaltrials.gov as #NCT00011648.
AB - 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, inwhom 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. This trial was registered at http://clinicaltrials.gov as #NCT00011648.
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U2 - 10.1182/blood-2009-09-244830
DO - 10.1182/blood-2009-09-244830
M3 - Article
C2 - 20335221
AN - SCOPUS:77955915246
SN - 0006-4971
VL - 116
SP - 109
EP - 112
JO - Blood
JF - Blood
IS - 1
ER -