Abstract
BackgroundPPHN is associated with decreased lung angiogenesis and impaired pulmonary vasodilatation at birth. Prostanoids are important modulators of vascular tone and angiogenesis. We hypothesized that altered levels of prostacyclin (PGI2), a potent vasodilator, and thromboxane (TXA2), a vasoconstrictor, contribute to impaired angiogenesis of pulmonary artery endothelial cells (PAEC) in PPHN.MethodsPAEC were isolated from fetal lambs with PPHN induced by prenatal ductus arteriosus constriction or sham operated controls. Expression and activity of PGI2 synthase (PGIS) and TXA2 synthase (TXAS), expression of cyclooxygenases 1 and 2 (COX-1 and COX-2) and the role of PGIS/TXAS alterations in angiogenesis were investigated in PAEC from PPHN and control lambs.ResultsPGIS protein and activity were decreased and PGIS protein tyrosine nitration was increased in PPHN PAEC. In contrast, TXAS protein and its stimulated activity were increased in PPHN PAEC. COX-1 and COX-2 proteins were decreased in PPHN PAEC. Addition of PGI2 improved in vitro tube formation by PPHN PAEC, whereas, indomethacin decreased tube formation by control PAEC. PGIS knockdown decreased the in vitro angiogenesis in control PAEC, whereas, TXAS knockdown increased the in vitro angiogenesis in PPHN PAEC.ConclusionReciprocal alterations in PGI2 and TXA2 may contribute to impaired angiogenesis in PPHN.
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