title: Endothelium-derived hyperpolarizing factor in preeclampsia: heterogeneous contribution, mechanisms, and morphological prerequisites.
abstract: We hypothesized that in preeclampsia (PE), contribution of endothelium-derived hyperpolarizing factor (EDHF) and the mechanism/s of its action differ from that in normal pregnancy (NP). We aimed to assess endothelial function and morphology in arteries from NP and PE with particular focus on EDHF. Arteries ( approximately 200 mum) were dissected from subcutaneous fat biopsies obtained from women undergoing cesarean section. With the use of wire myography, responses to the endothelium-dependent agonist bradykinin (BK) were determined before and after inhibition of pathways relevant to EDHF activity. The overall responses to BK in arteries from PE (n = 13) and NP (n = 17) were similar. However, in PE, EDHF-mediated relaxation was reduced (P < 0.05). All women within the PE group were divided into two subgroups: with more (group 1) or less (group 2) than 50% reduction of EDHF-typed responses after 18-alpha-glycyrrhetinic acid (an inhibitor of myoendothelial gap junctions, MEGJs). The division showed that 1) MEGJs are principally involved when the EDHF contribution is reduced; and 2) when the EDHF contribution is similar to that in NP, the H(2)O(2) and/or cytochrome P-450 epoxygenase products of arachidonic acid (AA), along with MEGJs, confer EDHF-mediated relaxation. In contrast, MEGJs were the main pathway for EDHF in NP. The abundant presence of MEGJs in arteries from NP but deficiency of them in PE was observed using transmission electron microscopy. We conclude that PE is associated with heterogeneous contribution of EDHF, and the mechanism behind EDHF-typed responses is mediated either by MEGJs alone or in combination with H(2)O(2) or cytochrome P-450 epoxygenase metabolites of AA.
authors.affiliation: Institution for Clinical Science, Intervention and Technology, Department of Obstetrics and Gynecology, Karolinska Institute, Karolinska University Hospital-Huddinge Campus, 14186 Stockholm, Sweden.
authors.forename: Leanid
authors.initials: L
authors.lastname: Luksha
authors.forename: Henry
authors.initials: H
authors.lastname: Nisell
authors.forename: Natallia
authors.initials: N
authors.lastname: Luksha
authors.forename: Marius
authors.initials: M
authors.lastname: Kublickas
authors.forename: Kjell
authors.initials: K
authors.lastname: Hultenby
authors.forename: Karolina
authors.initials: K
authors.lastname: Kublickiene
mesh_terms: D000293:Adolescent; D000328:Adult; D016718:Arachidonic Acid / Q000378:metabolism; D001158:Arteries / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D001685:Biological Factors / Q000378:metabolism*; D001706:Biopsy; D001920:Bradykinin / Q000494:pharmacology; D002317:Cardiovascular Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D017629:Gap Junctions / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D006034:Glycyrrhetinic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D046529:Microscopy, Electron, Transmission; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D011225:Pre-Eclampsia / Q000209:etiology* / Q000378:metabolism*; D011247:Pregnancy; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D001685:Biological Factors; D002317:Cardiovascular Agents; D004791:Enzyme Inhibitors; D014665:Vasodilator Agents; C067410:endothelium-dependent hyperpolarization factor; C119129:18alpha-glycyrrhetinic acid; D016718:Arachidonic Acid; D009569:Nitric Oxide; D006861:Hydrogen Peroxide; D006034:Glycyrrhetinic Acid; D001920:Bradykinin; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin