Angiotensin II Type 2 Receptor- and Acetylcholine-Mediated Relaxation Essential Contribution of Female Sex Hormones and Chromosomes

Bruno Seva Pessoa, Denise Slump, K Ibrahimi, Aldo Grefhorst, Richard van Veghel, Ingrid Van den Berg - Garrelds, Anton Roks, Steven Kushner, Jan Danser, Joep Esch

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Angiotensin-induced vasodilation, involving type 2 receptor (AT(2)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 AT(2)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 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 AT(2)R antagonist PD123319 revealed that this was because of a dilator AT(2)R-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, AT(2)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, AT(2)R-induced relaxation requires both estrogen and the XX chromosome sex complement, whereas only the latter is required for endothelium-derived hyperpolarizing factors.
Original languageUndefined/Unknown
Pages (from-to)396-402
Number of pages7
Issue number2
Publication statusPublished - 2015

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