title: Estrogen regulates endothelial migration via plasminogen activator inhibitor (PAI-1).
abstract: Endothelial plasminogen activator inhibitor (PAI-1) controls vascular remodeling, angiogenesis and fibrinolysis. PAI-1 blood levels in women are related to estrogen. The aim of this study was to characterize the signaling pathways through which estrogen regulates PAI-1 in endothelial cells. Furthermore, we aimed to investigate whether PAI-1 is implicated in the control of endothelial migration by estrogen. Cultured human umbilical vein endothelial cells (HUVECs) and ovariectomized rats were used to test the effects of 17β-estradiol (E(2)) on PAI-1 expression and its role on endothelial migration. At physiological concentrations, E(2) increases the expression of PAI-1 in HUVEC within 6-12 h through activation of a signaling cascade initiated by estrogen receptor α and involving G proteins, phosphatidylinositol-3-OH kinase and Rho-associated kinase II. ROCK-II activation turns into an over-expression of c-Jun and c-Fos that is required for E(2)-induced expression of PAI-1. Estrogen-induced PAI-1 expression is implicated in HUVEC horizontal migration. PAI-1 regulation is found also in vivo, in female rats, where ovariectomy is associated with reduced PAI-1 expression, while estrogen replacement counteracts this change. In conclusion, E(2) increases PAI-1 synthesis in human endothelial cells and in rodent aorta through a G protein-initiated signaling that targets early-immediate gene expression. This regulatory pathway is implicated in endothelial cell migration. These findings describe new mechanisms of action of estrogens in the vessels, which may be important for vascular remodeling and hemostasis.
authors.affiliation: Molecular and Cellular Gynecological Endocrinology Laboratory, Department of Reproductive Medicine and Child Development,  Division of Obstetrics and Gynecology,  University of Pisa, Via Roma 57, 56100 Pisa,  Italy.
authors.forename: Santhosh
authors.initials: S
authors.lastname: Gopal
authors.forename: Silvia
authors.initials: S
authors.lastname: Garibaldi
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Goglia
authors.forename: Kinga
authors.initials: K
authors.lastname: Polak
authors.forename: Giulia
authors.initials: G
authors.lastname: Palla
authors.forename: Stefania
authors.initials: S
authors.lastname: Spina
authors.forename: Andrea R
authors.initials: AR
authors.lastname: Genazzani
authors.forename: Alessandro D
authors.initials: AD
authors.lastname: Genazzani
authors.forename: Tommaso
authors.initials: T
authors.lastname: Simoncini
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism*; D002465:Cell Movement; D002478:Cells, Cultured; D004958:Estradiol / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics; D004967:Estrogens / Q000097:blood / Q000378:metabolism; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000502:physiology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000096:biosynthesis / Q000235:genetics; D010052:Ovariectomy; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D047628:Estrogen Receptor alpha; D004967:Estrogens; D017395:Plasminogen Activator Inhibitor 1; D016760:Proto-Oncogene Proteins c-fos; D034741:RNA, Small Interfering; D004958:Estradiol; D058539:Phosphatidylinositol 3-Kinase; D054460:rho-Associated Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D019204:GTP-Binding Proteins