Reproductive age women (5–10%) are affected by the polycystic ovarian syndrome (PCOS), a diagnosis which confers lifelong cardiovascular and reproductive health implications. Plasminogen activator inhibitor-1 (PAI-1), the main physiological inhibitor of plasminogen activation, is consistently elevated in women with PCOS, regardless of metabolic status. Interestingly, the plasminogen system has long been implicated in proteolytic processes within the dynamic ovary. A non-physiologic elevation in PAI-1 may thus contribute systemically to endothelial dysfunction and locally to abnormal ovarian phenotype and function. We herein characterize the phenotypic alterations in ovaries from transgenic mice, which constitutively express a stable form of human PAI-1 and determine the plasma testosterone level in these mice as opposed to their unaffected counterparts. Over half of the ovaries from transgenic mice were found to contain large cystic structures, in contrast to wild-type controls of the same genetic background (53% (N = 17) vs 5% (N = 22); P = 0.001). Plasma testosterone was nearly twofold elevated in transgenic female mice versus wild-type females (0.312 ng/ml ± 0.154 (N = 10) vs 0.181 ng/ml ± 0.083 (N = 8); P = 0.014). An elevation in PAI-1 therefore appears to predispose mice to the development of this abnormal architecture, which in turn is associated with an increase in plasma testosterone. Therefore, we propose that an inappropriate elevation in PAI-1 contributes to the development of polycystic structures; these findings may thus reorient the efforts aimed at the development of therapeutic agents for the treatment of this increasingly common syndrome.
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Jessica K Devin, Joyce E Johnson, Mesut Eren, Linda A Gleaves, William S Bradham, John R Bloodworth Jr, and Douglas E Vaughan
Ricardo Núñez Miguel, Paul Sanders, Lloyd Allen, Michele Evans, Matthew Holly, William Johnson, Andrew Sullivan, Jane Sanders, Jadwiga Furmaniak, and Bernard Rees Smith
Determination of the full-length thyroid-stimulating hormone receptor (TSHR) structure by cryo-electron microscopy (cryo-EM) is described. The TSHR complexed with human monoclonal TSHR autoantibody K1-70™ (a powerful inhibitor of TSH action) was detergent solubilised, purified to homogeneity and analysed by cryo-EM. The structure (global resolution 3.3 Å) is a monomer with all three domains visible: leucine-rich domain (LRD), hinge region (HR) and transmembrane domain (TMD). The TSHR extracellular domain (ECD, composed of the LRD and HR) is positioned on top of the TMD extracellular surface. Extensive interactions between the TMD and ECD are observed in the structure, and their analysis provides an explanation of the effects of various TSHR mutations on TSHR constitutive activity and on ligand-induced activation. K1-70™ is seen to be well clear of the lipid bilayer. However, superimposition of M22™ (a human monoclonal TSHR autoantibody which is a powerful stimulator of the TSHR) on the cryo-EM structure shows that it would clash with the bilayer unless the TSHR HR rotates upwards as part of the M22™ binding process. This rotation could have an important role in TSHR stimulation by M22™ and as such provides an explanation as to why K1-70™ blocks the binding of TSH and M22™ without activating the receptor itself.