title: Estradiol and dihydrotestosterone regulate endothelial cell barrier function after hypergravity-induced alterations in MAPK activity.
abstract: Postflight orthostatic intolerance (POI) was reported to be higher in female than male astronauts and may result from sex-dependent differences in endothelial cell (EC) barrier permeability. Here the effect of 17beta-estradiol (E(2)) and dihydrotestosterone (DHT) on the expression of the tight junction protein occludin, EC barrier function, and MAPK activation over time was tested after subjecting human umbilical vein EC (HUVEC) to brief hypergravity identical to that experienced by astronauts during liftoff (LO) into space. After LO hypergravity, HUVEC showed a time-dependent decrease in occludin correlating with an increase in paracellular permeability and a decrease in transendothelial electrical resistance, indicating a decrease in EC barrier function. LO hypergravity inhibited MAPK activation, which remained suppressed 4 h after LO. Inhibition of MAPK activation correlated with decreased phosphotyrosine occludin, decreased cytochrome-c oxidase activity, and increased paracellular permeability, suggesting a mechanism by which LO hypergravity decreased EC barrier function. Time-dependent differences in MAPK activation, decreased occludin, and EC barrier function between HUVEC treated with E(2) vs. DHT were observed. HUVEC showed delayed activation of MAPK with DHT, i.e., 4 h rather than 2 h for E(2), which correlated with decreased paracellular permeability and the observed sex differences in POI in astronauts. These data temporally separate E(2) and DHT effects in HUVEC and provide evidence for the possible protective roles of sex steroids on EC function after brief exposure to low hypergravity.
authors.affiliation: Dept of Biochemistry and Molecular Biology and Center for Genetics and Molecular Medicine, School of Medicine, University of Louisville, KY 40292, USA.
authors.forename: Wasana K
authors.initials: WK
authors.lastname: Sumanasekera
authors.forename: Gamini U
authors.initials: GU
authors.lastname: Sumanasekera
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Mattingly
authors.forename: Susan M
authors.initials: SM
authors.lastname: Dougherty
authors.forename: Robert S
authors.initials: RS
authors.lastname: Keynton
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Klinge
mesh_terms: D002199:Capillary Permeability / Q000187:drug effects; D002478:Cells, Cultured; D013196:Dihydrotestosterone / Q000378:metabolism* / Q000494:pharmacology; D017097:Electric Impedance; D003576:Electron Transport Complex IV / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D004789:Enzyme Activation; D004958:Estradiol / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D006801:Humans; D018471:Hypergravity; D007024:Hypotension, Orthostatic / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D062793:Occludin; D010766:Phosphorylation; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D012737:Sex Factors; D013026:Space Flight; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors; D014443:Tyrosine / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; D013196:Dihydrotestosterone; D014443:Tyrosine; D004958:Estradiol; D011451:Prostaglandin-Endoperoxide Synthases; D003576:Electron Transport Complex IV; D020928:Mitogen-Activated Protein Kinases