title: Reduced estradiol-induced vasodilation and poly-(ADP-ribose) polymerase (PARP) activity in the aortas of rats with experimental polycystic ovary syndrome (PCOS).
abstract: Polycystic ovary syndrome (PCOS) is a complex endocrine disorder characterized by hyperandrogenism and insulin resistance, both of which have been connected to atherosclerosis. Indeed, an increased risk of clinical manifestations of arterial vascular diseases has been described in PCOS. On the other hand endothelial dysfunction can be detected early on, before atherosclerosis develops. Thus we assumed that vascular dysfunction is also related directly to the hormonal imbalance rather than to its metabolic consequences. To detect early functional changes, we applied a novel rodent model of PCOS: rats were either sham operated or hyperandrogenism was achieved by implanting subcutaneous pellets of dihydrotestosterone (DHT). After ten weeks, myograph measurements were performed on isolated aortic rings. Previously we described an increased contractility to norepinephrine (NE). Here we found a reduced immediate relaxation to estradiol treatment in pre-contracted aortic rings from hyperandrogenic rats. Although the administration of vitamin D3 along with DHT reduced responsiveness to NE, it did not restore relaxation to estradiol. Poly-(ADP-ribose) polymerase (PARP) activity was assessed by poly-ADP-ribose immunostaining. Increased PAR staining in ovaries and circulating leukocytes from DHT rats showed enhanced DNA damage, which was reduced by concomitant vitamin D3 treatment. Surprisingly, PAR staining was reduced in both the endothelium and vascular smooth muscle cells of the aorta rings from hyperandrogenic rats. Thus in the early phase of PCOS, vascular tone is already shifted towards vasoconstriction, characterized by reduced vasorelaxation and vascular dysfunction is concomitant with altered PARP activity. Based on our findings, PARP inhibitors might have a future perspective in restoring metabolic disorders in PCOS.
authors.affiliation: Cardiology Unit, Bajcsy-Zsilinszky Hospital, Budapest, Hungary. gmasszi@bni.hu
authors.forename: Gabriella
authors.initials: G
authors.lastname: Masszi
authors.forename: Eszter Maria
authors.initials: EM
authors.lastname: Horvath
authors.forename: Robert
authors.initials: R
authors.lastname: Tarszabo
authors.forename: Rita
authors.initials: R
authors.lastname: Benko
authors.forename: Agnes
authors.initials: A
authors.lastname: Novak
authors.forename: Anna
authors.initials: A
authors.lastname: Buday
authors.forename: Anna-Maria
authors.initials: AM
authors.lastname: Tokes
authors.forename: Gyorgy L
authors.initials: GL
authors.lastname: Nadasy
authors.forename: Peter
authors.initials: P
authors.lastname: Hamar
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Benyó
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Varbiro
mesh_terms: D000818:Animals; D001011:Aorta / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D002762:Cholecalciferol / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D004958:Estradiol / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D011085:Polycystic Ovary Syndrome / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects*; D014815:Vitamins / Q000494:pharmacology
chemical_list: D004967:Estrogens; D014815:Vitamins; D002762:Cholecalciferol; D011064:Poly Adenosine Diphosphate Ribose; D004958:Estradiol; D011065:Poly(ADP-ribose) Polymerases
references.citation: Br J Pharmacol. 1999 Jan;126(1):159-68
references.pmid: 10051132
references.citation: Am J Physiol Heart Circ Physiol. 2010 Aug;299(2):H386-95
references.pmid: 20511416
references.citation: Eur J Pharmacol. 2010 Sep 25;643(2-3):254-9
references.pmid: 20599910
references.citation: J Clin Endocrinol Metab. 2010 May;95(5):2038-49
references.pmid: 20375205
references.citation: Int J Cardiol. 2008 Jan 24;123(3):366-8
references.pmid: 17689746
references.citation: J Immunol. 2009 Jun 1;182(11):7297-306
references.pmid: 19454727
references.citation: Mol Med. 2006 Jul-Aug;12(7-8):143-52
references.pmid: 17088946
references.citation: Am J Pathol. 2008 Jul;173(1):2-13
references.pmid: 18535182
references.citation: Am J Physiol Heart Circ Physiol. 2010 May;298(5):H1301-7
references.pmid: 20228257
references.citation: J Thromb Thrombolysis. 2009 May;27(4):359-64
references.pmid: 18535785
references.citation: Am J Physiol Regul Integr Comp Physiol. 2004 Feb;286(2):R233-49
references.pmid: 14707008
references.citation: J Clin Endocrinol Metab. 2005 Sep;90(9):5088-95
references.pmid: 15985492
references.citation: Methods Mol Biol. 2011;780:267-75
references.pmid: 21870266
references.citation: Life Sci. 2007 May 16;80(23):2170-2180
references.pmid: 17499811
references.citation: Cell Mol Life Sci. 2005 Apr;62(7-8):751-9
references.pmid: 15868400
references.citation: Med Res Rev. 2001 Mar;21(2):171-84
references.pmid: 11223864
references.citation: Clin Sci (Lond). 2000 Jun;98(6):661-5
references.pmid: 10814602
references.citation: Trends Pharmacol Sci. 2006 Dec;27(12):626-30
references.pmid: 17055069
references.citation: J Clin Endocrinol Metab. 2003 Jun;88(6):2562-8
references.pmid: 12788855
references.citation: Int J Mol Med. 2007 Jun;19(6):947-52
references.pmid: 17487428
references.citation: Am J Physiol Heart Circ Physiol. 2008 Jun;294(6):H2444-55
references.pmid: 18310519
references.citation: Coron Artery Dis. 2000 May;11(3):253-9
references.pmid: 10832559
references.citation: Hum Reprod Update. 2011 Jul-Aug;17(4):495-500
references.pmid: 21335359
references.citation: Cardiovasc Drug Rev. 2007 Fall;25(3):235-60
references.pmid: 17919258
references.citation: Curr Vasc Pharmacol. 2005 Jul;3(3):209-14
references.pmid: 16026317
references.citation: Endocrinology. 2007 Aug;148(8):3781-91
references.pmid: 17495003
references.citation: Nutr Metab Cardiovasc Dis. 2010 Nov;20(9):641-6
references.pmid: 19836216
references.citation: Circ Res. 2001 Oct 12;89(8):684-91
references.pmid: 11597991
references.citation: Exp Neurol. 2009 May;217(1):210-8
references.pmid: 19268668
references.citation: Nutr Res. 2012 Mar;32(3):195-201
references.pmid: 22464806
references.citation: Pharmacol Rev. 2002 Sep;54(3):375-429
references.pmid: 12223530
references.citation: Diabetologia. 2009 May;52(5):952-61
references.pmid: 19263033
references.citation: Mol Med. 2006 Sep-Oct;12(9-10):221-8
references.pmid: 17225870
references.citation: J Clin Endocrinol Metab. 2011 Jun;96(6):1827-34
references.pmid: 21450988
references.citation: Complement Ther Clin Pract. 2012 May;18(2):85-8
references.pmid: 22500844
references.citation: Endocr Pract. 2005 Mar-Apr;11(2):126-34
references.pmid: 15915567
references.citation: J Cereb Blood Flow Metab. 2005 Apr;25(4):502-12
references.pmid: 15689952
references.citation: J Pharmacol Exp Ther. 2005 Nov;315(2):812-20
references.pmid: 16079296
references.citation: Womens Health (Lond). 2010 Sep;6(5):737-52
references.pmid: 20887171
references.citation: N Engl J Med. 1999 Jun 10;340(23):1801-11
references.pmid: 10362825