Regulation of vascular tone and remodeling of the ductus arteriosus

DOI Web Site PubMed 被引用文献22件 参考文献63件
  • Yokoyama Utako
    Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine
  • Minamisawa Susumu
    Department of Life Science and Medical Bioscience, Waseda University Graduate School of Advanced Science and Engineering
  • Ishikawa Yoshihiro
    Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine

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The ductus arteriosus (DA), a fetal arterial connection between the main pulmonary artery and the descending aorta, normally closes immediately after birth. The DA is a normal and essential fetal structure. However, it becomes abnormal if it remains patent after birth. Closure of the DA occurs in two phases: functional closure of the lumen within the first hours after birth by smooth muscle constriction, and anatomic occlusion of the lumen over the next several days due to extensive neointimal thickening in human DA. There are several events that promote the DA constriction immediately after birth: (a) an increase in arterial oxygen tension, (b) a dramatic decline in circulating prostaglandinE2 (PGE2), (c) a decrease in blood pressure within the DA lumen, and (d) a decrease in the number of PGE2 receptors in the DA wall. Anatomical closure of the DA is associated with the formation of intimal thickening, which are characterized by (a) an area of subendothelial deposition of extracellular matrix, (b) the disassembly of the internal elastic lamina and loss of elastic fiber in the medial layer, and (c) migration into the subendothelial space of undifferentiated medial smooth muscle cells. In addition to the well-known vasodilatory role of PGE2, our findings uncovered the role of PGE2 in anatomical closure of the DA. Chronic PGE2-EP4-cyclic AMP (cAMP)-protein kinase A (PKA) signaling during gestation induces vascular remodeling of the DA to promote hyaluronan-mediated intimal thickening and structural closure of the vascular lumen. A novel target of cAMP, Epac, has an acute promoting effect on smooth muscle cell migration without hyaluronan production and thus intimal thickening in the DA. Both EP4-cAMP downstream targets, Epac and PKA, regulate vascular remodeling in the DA.<br>

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