Faculty Collaboration Database

Altered prostanoid metabolism contributes to impaired angiogenesis in persistent pulmonary hypertension in a fetal lamb model. Pediatr Res 2015 Mar;77(3):455-62

Date

12/19/2014

Pubmed ID

25521916

Pubmed Central ID

PMC4346417

DOI

10.1038/pr.2014.209

Scopus ID

2-s2.0-84938515685 (requires institutional sign-in at Scopus site)   26 Citations

Abstract

BACKGROUND: Persistent pulmonary hypertension of the newborn (PPHN) 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 A₂ (TXA₂), a vasoconstrictor, contribute to impaired angiogenesis of pulmonary artery endothelial cells (PAEC) in PPHN.

METHODS: PAEC were isolated from fetal lambs with PPHN induced by prenatal ductus arteriosus constriction or from 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.

RESULTS: PGIS 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.

CONCLUSION: Reciprocal alterations in PGI₂ and TXA₂ may contribute to impaired angiogenesis in PPHN.

Author List

Mahajan CN, Afolayan AJ, Eis A, Teng RJ, Konduri GG

Authors

Adeleye James Afolayan MBBS Associate Professor in the Pediatrics department at Medical College of Wisconsin
Girija Ganesh Konduri MD Chief, Professor in the Pediatrics department at Medical College of Wisconsin
Ru-Jeng Teng MD Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Blotting, Western
Cyclooxygenase 1
Cyclooxygenase 2
Cytochrome P-450 Enzyme System
Endothelial Cells
Epoprostenol
Fetus
Gene Knockdown Techniques
Immunoprecipitation
Indomethacin
Intramolecular Oxidoreductases
Neovascularization, Physiologic
Persistent Fetal Circulation Syndrome
Pulmonary Artery
Sheep
Statistics, Nonparametric
Thromboxane A2
Thromboxane-A Synthase