title: Angiotensin II type 2 receptor- and acetylcholine-mediated relaxation: essential contribution of female sex hormones and chromosomes.
abstract: Angiotensin-induced vasodilation, involving type 2 receptor (AT2R)-induced generation of nitric oxide (NO; by endothelial NO synthase) and endothelium-derived hyperpolarizing factors, may be limited to women. To distinguish the contribution of female sex hormones and chromosomes to AT2R function and endothelium-derived hyperpolarizing factor-mediated vasodilation, we made use of the four-core genotype model, where the testis-determining Sry gene has been deleted (Y(-)) from the Y chromosome, allowing XY(-) mice to develop a female gonadal phenotype. Simultaneously, by incorporating the Sry gene onto an autosome, XY(-)Sry and XXSry transgenic mice develop into gonadal male mice. Four-core genotype mice underwent a sham or gonadectomy (GDX) operation, and after 8 weeks, iliac arteries were collected to assess vascular function. XY(-)Sry male mice responded more strongly to angiotensin than XX female mice, and the AT2R antagonist PD123319 revealed that this was because of a dilator AT2R-mediated effect occurring exclusively in XX female mice. The latter could not be demonstrated in XXSry male and XY(-) female mice nor in XX female mice after GDX, suggesting that it depends on both sex hormones and chromosomes. Indeed, treating C57bl/6 GDX male mice with estrogen could not restore angiotensin-mediated, AT2R-dependent relaxation. To block acetylcholine-induced relaxation of iliac arteries obtained from four-core genotype XX mice, both endothelial NO synthase and endothelium-derived hyperpolarizing factor inhibition were required, whereas in four-core genotype XY animals, endothelial NO synthase inhibition alone was sufficient. These findings were independent of gonadal sex and unaltered after GDX. In conclusion, AT2R-induced relaxation requires both estrogen and the XX chromosome sex complement, whereas only the latter is required for endothelium-derived hyperpolarizing factors.
authors.affiliation: From the Division of Vascular Medicine and Pharmacology (B.S.P., K.I., R.v.V., I.M.G., A.J.M.R., A.H.J.D., J.H.M.v.E.) and Division of Endocrinology, Department of Internal Medicine (A.G.), and Department of Psychiatry (D.E.S., S.A.K.), Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Bruno Sevá
authors.initials: BS
authors.lastname: Pessôa
authors.affiliation: From the Division of Vascular Medicine and Pharmacology (B.S.P., K.I., R.v.V., I.M.G., A.J.M.R., A.H.J.D., J.H.M.v.E.) and Division of Endocrinology, Department of Internal Medicine (A.G.), and Department of Psychiatry (D.E.S., S.A.K.), Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Denise E
authors.initials: DE
authors.lastname: Slump
authors.affiliation: From the Division of Vascular Medicine and Pharmacology (B.S.P., K.I., R.v.V., I.M.G., A.J.M.R., A.H.J.D., J.H.M.v.E.) and Division of Endocrinology, Department of Internal Medicine (A.G.), and Department of Psychiatry (D.E.S., S.A.K.), Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Khatera
authors.initials: K
authors.lastname: Ibrahimi
authors.affiliation: From the Division of Vascular Medicine and Pharmacology (B.S.P., K.I., R.v.V., I.M.G., A.J.M.R., A.H.J.D., J.H.M.v.E.) and Division of Endocrinology, Department of Internal Medicine (A.G.), and Department of Psychiatry (D.E.S., S.A.K.), Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Aldo
authors.initials: A
authors.lastname: Grefhorst
authors.affiliation: From the Division of Vascular Medicine and Pharmacology (B.S.P., K.I., R.v.V., I.M.G., A.J.M.R., A.H.J.D., J.H.M.v.E.) and Division of Endocrinology, Department of Internal Medicine (A.G.), and Department of Psychiatry (D.E.S., S.A.K.), Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Richard
authors.initials: R
authors.lastname: van Veghel
authors.affiliation: From the Division of Vascular Medicine and Pharmacology (B.S.P., K.I., R.v.V., I.M.G., A.J.M.R., A.H.J.D., J.H.M.v.E.) and Division of Endocrinology, Department of Internal Medicine (A.G.), and Department of Psychiatry (D.E.S., S.A.K.), Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Ingrid M
authors.initials: IM
authors.lastname: Garrelds
authors.affiliation: From the Division of Vascular Medicine and Pharmacology (B.S.P., K.I., R.v.V., I.M.G., A.J.M.R., A.H.J.D., J.H.M.v.E.) and Division of Endocrinology, Department of Internal Medicine (A.G.), and Department of Psychiatry (D.E.S., S.A.K.), Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Anton J M
authors.initials: AJ
authors.lastname: Roks
authors.affiliation: From the Division of Vascular Medicine and Pharmacology (B.S.P., K.I., R.v.V., I.M.G., A.J.M.R., A.H.J.D., J.H.M.v.E.) and Division of Endocrinology, Department of Internal Medicine (A.G.), and Department of Psychiatry (D.E.S., S.A.K.), Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Kushner
authors.affiliation: From the Division of Vascular Medicine and Pharmacology (B.S.P., K.I., R.v.V., I.M.G., A.J.M.R., A.H.J.D., J.H.M.v.E.) and Division of Endocrinology, Department of Internal Medicine (A.G.), and Department of Psychiatry (D.E.S., S.A.K.), Erasmus MC, Rotterdam, The Netherlands. a.danser@erasmusmc.nl.
authors.forename: A H Jan
authors.initials: AH
authors.lastname: Danser
authors.affiliation: From the Division of Vascular Medicine and Pharmacology (B.S.P., K.I., R.v.V., I.M.G., A.J.M.R., A.H.J.D., J.H.M.v.E.) and Division of Endocrinology, Department of Internal Medicine (A.G.), and Department of Psychiatry (D.E.S., S.A.K.), Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Joep H M
authors.initials: JH
authors.lastname: van Esch
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology / Q000502:physiology*; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D004967:Estrogens / Q000502:physiology*; D005260:Female; D024282:Genes, sry / Q000235:genetics; D005838:Genotype; D007083:Iliac Artery / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism; D010641:Phenotype; D044139:Receptor, Angiotensin, Type 2 / Q000502:physiology*; D012737:Sex Factors; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D014960:X Chromosome / Q000502:physiology*
chemical_list: D004967:Estrogens; D044139:Receptor, Angiotensin, Type 2; D000804:Angiotensin II; D009569:Nitric Oxide; D000109:Acetylcholine
keywords: acetylcholine; angiotensinogen; angiotensins; genes, sry; receptor, angiotensin, type 2