title: 17beta-estradiol mediated protection against vascular leak after hemorrhagic shock: role of estrogen receptors and apoptotic signaling.
abstract: Vascular hyperpermeability is a clinical complication associated with hemorrhagic shock (HS) and occurs mainly because of the disruption of the adherens junctional complex. The objective of this study was to understand the role of 17beta-estradiol in HS-induced hyperpermeability particularly focusing on estrogen receptors. In male Sprague-Dawley rats, HS was induced by withdrawing blood to reduce the mean arterial pressure to 40 mmHg for 1 hour followed by 1 hour of resuscitation to 90 mmHg. The study groups were 17beta-estradiol, tamoxifen, fulvestrant plus 17beta-estradiol, propyl pyrazole triol plus 17beta-estradiol, and diarylpropionitrile plus 17beta-estradiol. Intravital microscopy was used to study changes in mesenteric postcapillary venules. Mitochondrial reactive oxygen species formation was studied in vivo using dihydrorhodamine 123. The mitochondrial transmembrane potential was studied using the fluorescent cationic probe 5,5',6,6'tetrachloro-1,1',3,3'tetraethylbenzimidazolyl carbocyanine iodide (JC-1). The mesenteric microvasculature was analyzed for cytochrome c levels by enzyme-linked immunosorbent assay and caspase-3 activity by a fluorometric assay. Our results demonstrated that 17beta-estradiol attenuated HS-induced hyperpermeability. Fulvestrant reversed this protective effect (P < 0.05). Tamoxifen 5 mg/kg attenuated HS-induced hyperpermeability, whereas 10 mg/kg induced permeability (P < 0.05). Both alpha and beta estrogen receptor agonists inhibited HS-induced hyperpermeability (P < 0.05). 17beta-Estradiol decreased HS-induced reactive oxygen species formation and restored mitochondrial transmembrane potential. 17beta-Estradiol decreased both cytosolic cytochrome c level and activation of caspase-3 (P < 0.05). These findings suggest that 17beta-estradiol protects the microvasculature after HS, and that this protection may be mediated through the alpha and beta estrogen receptors.
authors.affiliation: Department of Surgery, Texas A&M University Health Science Center, Temple, TX, USA. echilds@swmail.sw.org
authors.forename: Ed W
authors.initials: EW
authors.lastname: Childs
authors.forename: Binu
authors.initials: B
authors.lastname: Tharakan
authors.forename: Felicia A
authors.initials: FA
authors.lastname: Hunter
authors.forename: W Roy
authors.initials: WR
authors.lastname: Smythe
mesh_terms: D000818:Animals; D019559:Capillary Leak Syndrome / Q000209:etiology / Q000517:prevention & control*; D002199:Capillary Permeability / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use* / Q000633:toxicity; D020847:Estrogen Receptor Modulators / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000502:physiology*; D047629:Estrogen Receptor beta / Q000819:agonists / Q000502:physiology*; D000077267:Fulvestrant; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008643:Mesentery / Q000098:blood supply; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D009570:Nitriles / Q000008:administration & dosage / Q000494:pharmacology; D010636:Phenols; D011422:Propionates / Q000008:administration & dosage / Q000494:pharmacology; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D012771:Shock, Hemorrhagic / Q000150:complications / Q000503:physiopathology*; D013629:Tamoxifen / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D014699:Venules / Q000648:ultrastructure
chemical_list: C486182:2,3-bis(4-hydroxyphenyl)-propionitrile; D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D009570:Nitriles; D010636:Phenols; D011422:Propionates; D011720:Pyrazoles; D017382:Reactive Oxygen Species; D013629:Tamoxifen; C486184:4,4',4''-(4-propyl-((1)H)-pyrazole-1,3,5-triyl) tris-phenol; D000077267:Fulvestrant; D004958:Estradiol