title: Estrous cycle-dependent neurovascular dysfunction induced by angiotensin II in the mouse neocortex.
abstract: Female mice are protected from the cerebrovascular dysfunction induced by angiotensin II (Ang II), an effect attributed to estrogen. We examined whether such cerebrovascular protection from Ang II is related to the estrous cycle. Cerebral blood flow was monitored by laser-Doppler flowmetry in anesthetized (urethane-chloralose) C57BL/6 female mice equipped with a cranial window. The phase of the estrous cycle was determined by vaginal smear cytology and plasma estrogen measurement. Ang II (0.25 microg/kg per minute, IV, 30 to 45 minutes) elevated arterial pressure (15 to 20 mm Hg) equally across the estrous cycle. However, in proestrus and estrus, phases in which estrogen is relatively high, Ang II did not impair the increase in the cerebral blood flow induced by neural activity or by endothelium-dependent vasodilators (P>0.05 from vehicle). In contrast, in diestrus (lower estrogen), Ang II induced a marked cerebrovascular dysfunction comparable to that of male mice. For example, the cerebral blood flow responses to whisker stimulation and to the endothelium-dependent vasodilator acetylcholine were attenuated by 41+/-12% and 49+/-12%, respectively (P<0.05; n=6 per group). The protection from the cerebrovascular effects of Ang II in proestrus was abolished by the estrogen receptor inhibitor ICI182,780. Ang II also increased production of free radicals in cerebral blood vessels in diestrus (+116+/-13%; P<0.05) but not in proestrus and estrus (P>0.05 from control). Topical treatment with ICI182,780 reestablished Ang II-induced oxidative stress in proestrus (P>0.05 from diestrus). We conclude that the protection from the neurovascular dysfunction induced by acute administration of Ang II in females depends on the estrous cycle and may underlie the increased propensity to cerebrovascular damage associated with low estrogen states.
authors.affiliation: Division of Neurobiology, Weill Cornell Medical College, 407 East 61st St, New York, NY 10065, USA.
authors.forename: Carmen
authors.initials: C
authors.lastname: Capone
authors.forename: Josef
authors.initials: J
authors.lastname: Anrather
authors.forename: Teresa A
authors.initials: TA
authors.lastname: Milner
authors.forename: Costantino
authors.initials: C
authors.lastname: Iadecola
mesh_terms: D000704:Analysis of Variance; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002560:Cerebrovascular Circulation / Q000187:drug effects* / Q000502:physiology; D002561:Cerebrovascular Disorders / Q000503:physiopathology*; D004195:Disease Models, Animal; D045462:Endothelium-Dependent Relaxing Factors / Q000378:metabolism / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors*; D030762:Estrous Cycle / Q000187:drug effects* / Q000502:physiology; D005260:Female; D005609:Free Radicals / Q000378:metabolism; D017078:Laser-Doppler Flowmetry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019579:Neocortex / Q000187:drug effects* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D011336:Probability; D011897:Random Allocation; D012016:Reference Values; D012307:Risk Factors; D012680:Sensitivity and Specificity; D012737:Sex Factors
chemical_list: D045462:Endothelium-Dependent Relaxing Factors; D047628:Estrogen Receptor alpha; D005609:Free Radicals; D000804:Angiotensin II