The neurovascular dysfunction induced by angiotensin II in the mouse neocortex is sexually dimorphic

Abstract

Women are less susceptible to the cerebrovascular complications of hypertension, such as a stroke and vascular dementia. The mechanism of such protection may be related to a reduced vulnerability of women to the cerebrovascular actions of hypertension. To test this hypothesis, we used a model of hypertension based on infusion of angiotensin II (ANG II), an octapeptide that plays a key role in hypertension and produces cerebrovascular dysregulation. Cerebral blood flow (CBF) was monitored by laser-Doppler flowmetry in anesthetized (urethane-chloralose) C57BL/6J male and female mice equipped with a cranial window. ANG II administration (0.25 mug.kg(-1).min(-1) iv x 30-45 min) elevated arterial pressure equally in both sexes but attenuated the CBF increase induced by whisker stimulation or by the endothelium-dependent vasodilator acetylcholine (ACh) in male but not in female mice. The administration of ANG II for 7 days (2.74 mg.kg(-1).day(-1)), using osmotic minipumps, also attenuated these cerebrovascular responses in male, but not female, mice. The reduced susceptibility to the effect of ANG II in female mice was abolished by ovariectomy and reinstated by estrogen administration to ovariectomized mice. Administration of estrogen to male mice abolished the ANG II-induced attenuation of CBF responses. We conclude that female mice are less susceptible to the cerebrovascular dysregulation induced by ANG II, an effect related to estrogen. Such protection from the deleterious cerebrovascular effects of hypertension may play a role in the reduced vulnerability to the cerebrovascular complications of hypertension observed in women.

Gender Influences Cerebral Vascular Responses to Angiotensin II Through Nox2-Derived Reactive Oxygen Species

“…12 Furthermore, our findings are conceptually consistent with a recent study reporting that AngII administration attenuates the increase in cerebral blood flow induced by the endothelium-dependent vasodilator, acetylcholine, or whisker stimulation in male, but not female mice. 13 To test for a role for Nox2-containing NADPH-oxidases in the gender differences in cerebrovascular responses to AngII we studied Nox2-deficient mice. Firstly, we measured AngIIstimulated O 2 Ϫ production by cerebral arteries from WT and …”

“…11 Moreover, studies have reported a marked gender difference in the effects of AngII on mouse cerebral arteries. 12,13 However, the role of NADPHoxidase in such gender differences has not been evaluated. Therefore, we first tested whether gender influences the levels of ROS generated in cerebral arteries in response to AngII, and then whether contractile responses to AngII were similarly gender-dependent.…”

Ischemia-induced brain damage is enhanced in human renin and angiotensinogen double-transgenic mice

“…Regional CBF was measured during the MCAO surgery as described previously (6,14). Briefly, an incision was made in the scalp to expose the skull.…”

Sex differences in angiotensin signaling in bulbospinal neurons in the rat rostral ventrolateral medulla

“…Under the age of 45 yr, fewer women than men die from cardiovascular disease (1), a pattern which is reversed after menopause (52). Similar sex-associated differences exist in animal hypertension models: females develop hypertension later, and less severely, than males (11,35,62). Studies in humans and animal models indicate that central nervous system pathways play a critical role in the development and maintenance of hypertension (27).…”