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

N Sundaram, A Tailor, L Mendelsohn… - Blood, The Journal …, 2010 - ashpublications.org
N Sundaram, A Tailor, L Mendelsohn, J Wansapura, X Wang, T Higashimoto, MW Pauciulo…
Blood, The Journal of the American Society of Hematology, 2010ashpublications.org
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 …
Abstract
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. This trial was registered at http://clinicaltrials.gov as #NCT00011648.
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