title: Thromboxane A(2) receptor stimulation promotes closure of the rat ductus arteriosus through enhancing neointima formation.
abstract: Ductus arteriosus (DA) closure follows constriction and remodeling of the entire vessel wall. Patent ductus arteriosus occurs when the DA does not close after birth, and this condition is currently treated using cyclooxygenase inhibitors. However, the efficacy of cyclooxygenase inhibitors is often limited. Our previous study demonstrated that low-dose thromboxane A2 receptor (TP) stimulation constricted the DA with minimal adverse effects in rat neonates. However, its effect on DA remodeling remains unknown. In this study, we focused on the impact of the exogenous TP stimulation on the DA remodeling, especially intimal thickening. Using DA explants from rat fetuses at embryonic day 19 as a ex vivo model and primary cultured rat DA smooth muscle cells from embryonic day 21 as a in vitro model, we evaluated the effect of TP stimulation on the DA remodeling. The selective TP agonists U46619 and I-BOP promoted neointima formation in the ex vivo DA explants, and TP stimulation increased DA SMC migration in a dose-dependent manner. Both effects were inhibited by the selective TP antagonist SQ29548 or the siRNA against TP. TP stimulation also increased DA SMC proliferation in the presence of 10% fetal bovine serum. LC/MS/MS analysis revealed that TP stimulation increased secretion of several extracellular matrix proteins that may contribute to an increase in neointima formation. In conclusion, we uncovered that exogenous administration of TP agonist promotes neointima formation through the induction of migration and proliferation of DA SMC, which could contribute to DA closure and also to its vasoconstrictive action.
authors.affiliation: Department of Life Science and Medical Bioscience, Waseda University Graduate School of Advanced Science and Engineering, Tokyo, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Yokota
authors.affiliation: Department of Life Science and Medical Bioscience, Waseda University Graduate School of Advanced Science and Engineering, Tokyo, Japan; Department of Cell Physiology, Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Shiraishi
authors.affiliation: Department of Life Science and Medical Bioscience, Waseda University Graduate School of Advanced Science and Engineering, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Aida
authors.affiliation: Department of Life Science and Medical Bioscience, Waseda University Graduate School of Advanced Science and Engineering, Tokyo, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Iwai
authors.affiliation: Department of Life Science and Medical Bioscience, Waseda University Graduate School of Advanced Science and Engineering, Tokyo, Japan.
authors.forename: Norika Mengchia
authors.initials: NM
authors.lastname: Liu
authors.affiliation: Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Kanagawa, Japan.
authors.forename: Utako
authors.initials: U
authors.lastname: Yokoyama
authors.affiliation: Department of Life Science and Medical Bioscience, Waseda University Graduate School of Advanced Science and Engineering, Tokyo, Japan; Department of Cell Physiology, Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Minamisawa
mesh_terms: D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D004373:Ductus Arteriosus / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D058426:Neointima / Q000378:metabolism* / Q000473:pathology; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*
chemical_list: D016326:Extracellular Matrix Proteins; D012333:RNA, Messenger; D044244:Receptors, Thromboxane A2, Prostaglandin H2
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