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: Bruno Sevá Pessôa, Denise E Slump, Khatera Ibrahimi, Aldo Grefhorst, Richard van Veghel, Ingrid M Garrelds, Anton J M Roks, Steven A Kushner, A H Jan Danser, Joep H M van Esch
• Journal: Hypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 66 Issue 2 Pg. 396-402 (Aug 2015) ISSN: 1524-4563 [Electronic] United States
• PMID: 26056343 (Publication Type: Comparative Study, Journal Article)
• Copyright: © 2015 American Heart Association, Inc.

Chemical References

• Estrogens
• Receptor, Angiotensin, Type 2
• Angiotensin II
• Nitric Oxide
• Acetylcholine

Topics

• Acetylcholine (pharmacology, physiology)
• Angiotensin II (pharmacology)
• Animals
• Estrogens (physiology)
• Female
• Genes, sry (genetics)
• Genotype
• Iliac Artery (drug effects, physiology)
• Male
• Mice
• Mice, Inbred C57BL
• Models, Animal
• Muscle Relaxation (drug effects, physiology)
• Muscle, Smooth, Vascular (drug effects, physiology)
• Nitric Oxide (metabolism)
• Phenotype
• Receptor, Angiotensin, Type 2 (physiology)
• Sex Factors
• Vasodilation (drug effects, physiology)
• X Chromosome (physiology)