RESUMO
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.
Assuntos
Acetilcolina/fisiologia , Estrogênios/fisiologia , Relaxamento Muscular/fisiologia , Músculo Liso Vascular/fisiologia , Receptor Tipo 2 de Angiotensina/fisiologia , Cromossomo X/fisiologia , Acetilcolina/farmacologia , Angiotensina II/farmacologia , Animais , Feminino , Genes sry/genética , Genótipo , Artéria Ilíaca/efeitos dos fármacos , Artéria Ilíaca/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Óxido Nítrico/metabolismo , Fenótipo , Fatores Sexuais , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologiaRESUMO
A capacidade de proliferação e diferenciação das células progenitoras endoteliais (CPE) tornaram-nas candidatas ideais para a pesquisa de reparação de danos vasculares. Embora os resultados sejam animadores, há uma série de fatores responsáveis pelo número e função das CPE que permanecem desconhecidos. Limitações quanto à identificação e regulação dos fatores envolvidos são encontradas, e as estratégias para reverter os danos vasculares são generalizadas. Portanto, há ainda um grande caminho até que as CPE sejam usadas de forma segura e promovam uma efetiva reparação.
The proliferation and differentiation capabilities of endothelial progenitor cells (EPC) make them ideal candidates for vascular damage repair research.Despite encouraging findings, several factors affecting the numbers and functions of these cells are still unknown, imposing constraints on the identificationand regulation of the factors involved, while strategies for reversing vascular damage are widespread. There is thus still a long way to go before EPCs can be used safely for effective repairs.
