Angiotensin II Type 2 Receptor– and Acetylcholine-Mediated Relaxation
Essential Contribution of Female Sex Hormones and Chromosomes
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.
- Received February 5, 2015.
- Revision received February 16, 2013.
- Accepted May 4, 2015.
- © 2015 American Heart Association, Inc.