E lastic fibers are the largest structures in the extracellular matrix. Beginning with the onset of pulsatile blood flow in the developing aorta and pulmonary artery, smooth muscle cells (SMCs) in the vessel wall produce a complex extracellular matrix that ultimately defines the mechanical properties that are critical for proper function of the neonatal and adult vascular system. 1 As such, hemodynamics and mechanical stress are considered to be the main regulators in the formation of the vascular elastic fiber system during development. 2 Clinical Perspective on p 496The ductus arteriosus (DA) and its connecting elastic arteries (ie, the descending aorta and the main pulmonary trunk) are exposed to essentially the same mechanical forces and hemodynamics. However, since 1914, it has been widely recognized in multiple species that the DA exhibits sparse elastic fibers in the middle layer compared with adjacent elastic arteries, as well as disassembly and fragmentation of the internal elastic lamina. [3][4][5][6][7][8] In the human fetal aorta, newly synthesized uncrosslinked elastin appears at 23 weeks of gestational age to be unevenly distributed on the surface of microfibrils, where it forms continuous strips of variable width. 9 However, the DA exhibits fewer elastic fibers than the aorta. 4,6 This decreased elastogenesis is the hallmark of the vascular remodeling of the DA in humans and a variety of other species. [3][4][5][6][7] It has been suggested that this muscular phenotype of the DA allows it to collapse easily at birth when prostaglandin E 2 (PGE 2 ) is withdrawn and blood flow between the aorta and the pulmonary artery is reduced, thereby permitting immediate postnatal closure of the DA. Conversely, it is known that abnormalities of elastic fibers and elastic lamina are primarily responsible for the persistence of the DA in some human cases.10,11 These abnormalities likely prevent intimal cushion formation and make it difficult to collapse the arterial wall. Therefore, it is 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 E 2 (PGE 2 ) 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 microscopi...

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.