title: Growth differentiation factor 15 impairs aortic contractile and relaxing function through altered caveolar signaling of the endothelium.
abstract: Growth differentiation factor 15 (GDF15) is an independent predictor of cardiovascular disease, and increased GDF15 levels have been associated with endothelial dysfunction in selected patients. We therefore investigated whether GDF15 modulates endothelial function in aortas of wild-type (WT) and GDF15 knockout (KO) mice. Vascular contractions to phenylephrine and relaxation to ACh were assessed in aortas obtained from healthy WT and GDF15 KO mice. The effects of GDF15 pretreatment and the involvement of ROS or caveolae were determined. Phenylephrine-induced contractions and ACh-mediated relaxations were similar in WT and GDF15 KO mice. Pretreatment with GDF15 inhibited contraction and relaxation in both groups. Inhibition of contraction by GDF15 was absent in denuded vessels or after blockade of nitric oxide (NO) synthase. Relaxation in WT mice was mediated mainly through NO and an unidentified endothelium-derived hyperpolarizin factor (EDHF), whereas GDF15 KO mice mainly used prostaglandins and EDHF. Pretreatment with GDF15 impaired relaxation in WT mice by decreasing NO; in GDF15 KO mice, this was mediated by decreased action of prostaglandins. Disruption of caveolae resulted in a similar inhibition of vascular responses as GDF15. ROS inhibition did not affect vascular function. In cultured endothelial cells, GDF15 pretreatment caused a dissociation between caveolin-1 and endothelial NO synthase. In conclusion, GDF15 impairs aortic contractile and relaxing function through an endothelium-dependent mechanism involving altered caveolar endothelial NO synthase signaling.
authors.affiliation: Department of Clinical Pharmacology, University of Groningen, and University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Mazagova
authors.forename: Hendrik
authors.initials: H
authors.lastname: Buikema
authors.forename: Sjoerd W
authors.initials: SW
authors.lastname: Landheer
authors.forename: Peter
authors.initials: P
authors.lastname: Vavrinec
authors.forename: Azuwerus van
authors.initials: Av
authors.lastname: Buiten
authors.forename: Robert H
authors.initials: RH
authors.lastname: Henning
authors.forename: Leo E
authors.initials: LE
authors.lastname: Deelman
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D021941:Caveolae / Q000502:physiology; D051242:Caveolin 1 / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D055436:Growth Differentiation Factor 15 / Q000235:genetics* / Q000378:metabolism* / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D054411:Receptors, Leptin / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
chemical_list: C495540:CAV1 protein, human; D051242:Caveolin 1; C526141:Gdf15 protein, mouse; D055436:Growth Differentiation Factor 15; D017382:Reactive Oxygen Species; D054411:Receptors, Leptin; C515447:leptin receptor, mouse; D009569:Nitric Oxide; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III