title: 17 beta-estradiol transiently disrupts adherens junctions in endothelial cells.
abstract: Interendothelial junctions are important regulators of endothelial cell functions such as migration and proliferation, major features in angiogenesis, and endothelial cell monolayer wound healing. 17beta-estradiol regulates these functions in vivo and in vitro and also increases endothelial monolayer permeability as it results from impaired monolayer integrity and intercellular adhesion. We hypothesized that 17beta-estradiol affects these cell adhesion-dependent functions in endothelial cells by targeting the adherens junction complex. Here, we show that 17beta-estradiol increases uterine microvascular endothelial cell monolayer permeability and transiently redistributes interendothelial junction-forming proteins in endothelial cells. Concomitantly, adherens junction proteins are disconnected from the cytoskeleton and alpha-catenin, which links VE-cadherin to the cytoskeleton, is redistributed from the membrane and the adherens junction complex. Furthermore, 17beta-estradiol increased tyrosine phosphorylation of the adherens junction complex. These effects were inhibited by the estrogen receptor antagonist ICI 182,780 but could be provoked using non-cell membrane-permeable 17beta-estradiol-BSA in all cells tested, including EA.hy 926 cells, which have been shown unable to stimulate 17beta-estradiol-dependent gene transcription. Additionally, 17beta-estradiol treatment enhanced the angiogenic effect of vascular endothelial growth factor in an in vitro angiogenesis model, as a potential implication of the adherens junction disruption. Cotreatment with the Src-family kinase inhibitor PP2 prevented the redistribution and phosphorylation of the adherens junction proteins. Taken together, our data show that adherens junctions in endothelial cells are a downstream target of membrane-associated 17beta-estradiol signaling, possibly through Src-family kinases.
authors.affiliation: Department of Pediatrics, Northwestern University and Children's Memorial Research Cente, Chicago, Illinois, USA. tanja.groten@web.de
authors.forename: Tanja
authors.initials: T
authors.lastname: Groten
authors.forename: Amy A
authors.initials: AA
authors.lastname: Pierce
authors.forename: Arthur C
authors.initials: AC
authors.lastname: Huen
authors.forename: H William
authors.initials: HW
authors.lastname: Schnaper
mesh_terms: D022005:Adherens Junctions / Q000737:chemistry / Q000187:drug effects*; D015703:Antigens, CD; D015820:Cadherins / Q000032:analysis; D002199:Capillary Permeability / Q000187:drug effects; D002448:Cell Adhesion; D002450:Cell Communication / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects* / Q000648:ultrastructure; D004958:Estradiol / Q000494:pharmacology*; D006801:Humans; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000032:analysis; D021381:Protein Transport; D011960:Receptors, Estrogen / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D051178:alpha Catenin / Q000032:analysis; D019061:src-Family Kinases / Q000502:physiology; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D004958:Estradiol; D019000:Phosphotyrosine; D011960:Receptors, Estrogen; D042461:Vascular Endothelial Growth Factor A; D051178:alpha Catenin; D019061:src-Family Kinases; D000099152:Cadherin 5