Angiotensin II Type 2 Receptor– and Acetylcholine-Mediated Relaxation: Essential Contribution of Female Sex Hormones and Chromosomes. Issue 2 (August 2015)

• Record Type: Journal Article
• Authors: Pessôa, Bruno Sevá; Slump, Denise E.; Ibrahimi, Khatera; Grefhorst, Aldo; van Veghel, Richard; Garrelds, Ingrid M.; Roks, Anton J.M.; Kushner, Steven A.; Danser, A.H. Jan; van Esch, Joep H.M.
• Is Part Of: Hypertension. Volume 66:Issue 2(2015:Aug.)
• Publication Date: 2015-08
• Subjects: acetylcholine -- angiotensins -- angiotensinogen -- genes, sry -- receptor, angiotensin, type 2; Hypertension -- Periodicals; Hypertension -- Treatment -- Periodicals; 616.132005
• DOI: 10.1161/HYPERTENSIONAHA.115.05303
• Languages: English
• ISSNs: 0194-911X

Abstract

Abstract : Angiotensin-induced vasodilation, involving type 2 receptor (AT2 R)–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 AT2 R 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 XX Sry 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 AT2 R antagonist PD123319 revealed that this was because of a dilator AT2 R-mediated effect occurring exclusively in XX female mice. The latter could not be demonstrated in XX Sry 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, AT2 R-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, AT2 R-induced relaxation requires both estrogen and the XX chromosome sex complement, whereas only the latter is required for endothelium-derived hyperpolarizing factors. Abstract : Supplemental Digital Content is available in the text.