071 - Role for dysregulated endothelium- derived FGF2 signaling in progression of pulmonary hypertension - 05/12/08

Molecular events originating in pulmonary endothelial cells (P-ECs) may contribute to pulmonary-artery smooth-muscle-cell (PA-SMC) hyperplasia during progression of pulmonary hypertension (PH). Using cultured cells from patients with idiopathic PH (IPH) and controls, we found that PA-SMC proliferation elicited by serum- free medium of quiescent P-ECs was greater with P-ECs from patients who had IPH than from controls. FGF2 levels were markedly elevated in serum-free medium of P-ECs from patients with IPH compared to controls; TGF-béta, PDGF, or EGF levels were not different. P-EC exposure to small interfering RNA (siRNA) against FGF2 reduced the growth-stimulating effects of P-EC media, and reduction was greater with P-ECs from patients (-60%) than from controls (-10%). In patients with IPH, lung FGF2 expression was markedly elevated and predominated in the endothelium. Rats developing PH after monocrotaline injection exhibited marked elevation of lung FGF2. Repeated intravenous FGF2- siRNA administration abolished the lung FGF2 increase and prevented PA-SMC proliferation and PH development. FGF2-siRNA administration started 3 weeks after monocrotaline injection almost completely reversed established PH, extracellular matrix accumulation, and inflammation. Dysregulated endothelium-derived FGF2 signaling contributes to many components of PH progression, identifying FGF2 as a promising target for new treatments against PH.