Angiotensin-induced vasodilation, involving type 2 receptor (AT<inf>2</inf>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<inf>2</inf>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<sup>-</sup>) from the Y chromosome, allowing XY<sup>-</sup> mice to develop a female gonadal phenotype. Simultaneously, by incorporating the Sry gene onto an autosome, XY<sup>-</sup>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<sup>-</sup>Sry male mice responded more strongly to angiotensin than XX female mice, and the AT<inf>2</inf>R antagonist PD123319 revealed that this was because of a dilator AT<inf>2</inf>R-mediated effect occurring exclusively in XX female mice. The latter could not be demonstrated in XXSry male and XY<sup>-</sup> 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<inf>2</inf>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<inf>2</inf>R-induced relaxation requires both estrogen and the XX chromosome sex complement, whereas only the latter is required for endothelium-derived hyperpolarizing factors.

Acetylcholine, Angiotensinogen, Angiotensins, Genes, sry, Receptor, angiotensin, type 2,
Erasmus MC: University Medical Center Rotterdam

Sevá Pessôa, B, Slump, D.E, Ibrahimi, K, Grefhorst, A, van Veghel, R, Garrelds, I.M, … van Esch, J.H.M. (2015). Angiotensin II Type 2 Receptor- and Acetylcholine-Mediated Relaxation: Essential Contribution of Female Sex Hormones and Chromosomes. Hypertension, 66(2), 396–402. doi:10.1161/HYPERTENSIONAHA.115.05303