ABSTRACT
BACKGROUND: Elastic fiber formation begins in mid-gestation and increases dramatically during the last trimester in the great arteries, providing elasticity and thus preventing vascular wall structure collapse. However, the ductus arteriosus (DA), a fetal bypass artery between the aorta and pulmonary artery, exhibits lower levels of elastic fiber formation, which promotes vascular collapse and subsequent closure of the DA after birth. The molecular mechanisms for this inhibited elastogenesis in the DA, which is necessary for the establishment of adult circulation, remain largely unknown. METHODS AND RESULTS: Stimulation of the prostaglandin E2 (PGE2) receptor EP4 significantly inhibited elastogenesis and decreased lysyl oxidase (LOX) protein, which catalyzes elastin cross-links in DA smooth muscle cells (SMCs), but not in aortic SMCs. Aortic SMCs expressed much less EP4 than DASMCs. Adenovirus-mediated overexpression of LOX restored the EP4-mediated inhibition of elastogenesis in DASMCs. In EP4-knockout mice, electron microscopic examination showed that the DA acquired an elastic phenotype that was similar to the neighboring aorta. More importantly, human DA and aorta tissues from 7 patients showed a negative correlation between elastic fiber formation and EP4 expression, as well as between EP4 and LOX expression. The PGE2-EP4-c-Src-phospholipase C (PLC)γ-signaling pathway most likely promoted the lysosomal degradation of LOX. CONCLUSIONS: Our data suggest that PGE2 signaling inhibits elastogenesis in the DA, but not in the aorta, through degrading LOX protein. Elastogenesis is spatially regulated by PGE2-EP4 signaling in the DA.
Subject(s)
Dinoprostone/physiology , Ductus Arteriosus/physiology , Elastic Tissue/physiology , Elasticity/physiology , Receptors, Prostaglandin E, EP4 Subtype/physiology , Signal Transduction/physiology , Animals , Aorta/cytology , Aorta/physiology , CSK Tyrosine-Protein Kinase , Cells, Cultured , Ductus Arteriosus/cytology , Ductus Arteriosus/ultrastructure , Elastic Tissue/ultrastructure , Elastin/physiology , Humans , Infant, Newborn , Mice , Mice, Inbred C57BL , Mice, Knockout , Models, Animal , Myocytes, Smooth Muscle/cytology , Myocytes, Smooth Muscle/physiology , Myocytes, Smooth Muscle/ultrastructure , Phenotype , Phospholipase C gamma/physiology , Protein-Lysine 6-Oxidase/physiology , Rats , Rats, Wistar , Receptors, Prostaglandin E, EP4 Subtype/deficiency , Receptors, Prostaglandin E, EP4 Subtype/genetics , src-Family Kinases/physiologyABSTRACT
The ductus arteriosus (DA), a fetal arterial connection between the pulmonary artery and the aorta, has a character distinct from the adjacent arteries. We compared the transcriptional profiles of the DA and the aorta of Wistar rat fetuses on embryonic day 19 (preterm) and day 21 (near-term) using DNA microarray analyses. We found that 39 genes were expressed 2.5-fold greater in the DA than in the aorta. Growth hormone (GH) receptor (GHR) exhibited the most significant difference in expression. Then, we found that GH significantly promoted migration of DA smooth muscle cells (SMCs), thus enhancing the intimal cushion formation of the DA explants. GH also regulated the expression of cytoskeletal genes in DA SMCs, which may retain a synthetic phenotype in the smooth muscle-specific cytoskeletal genes. Thus, the present study revealed that GH-GHR signal played a role in the vascular remodeling of the DA.
