Loss of Female Sex Hormones Exacerbates Cerebrovascular and Cognitive Dysfunction in Aortic Banded Miniswine Through a Neuropeptide Y–Ca(2+)‐Activated Potassium Channel–Nitric Oxide Mediated Mechanism

BACKGROUND: Postmenopausal women represent the largest cohort of patients with heart failure with preserved ejection fraction, and vascular dementia represents the most common form of dementia in patients with heart failure with preserved ejection fraction. Therefore, we tested the hypotheses that the combination of cardiac pressure overload (aortic banding [AB]) and the loss of female sex hormones (ovariectomy [OVX]) impairs cerebrovascular control and spatial memory. METHODS AND RESULTS: Female Yucatan miniswine were separated into 4 groups (n=7 per group): (1) control, (2) AB, (3) OVX, and (4) AB‐OVX. Pigs underwent OVX and AB at 7 and 8 months of age, respectively. At 14 months, cerebral blood flow velocity and spatial memory (spatial hole‐board task) were lower in the OVX groups (P<0.05), with significant impairments in the AB‐OVX group (P<0.05). Resting carotid artery β stiffness and vascular resistance during central hypovolemia were increased in the AB‐OVX group (P<0.05), and blood flow recovery after central hypovolemia was reduced in both OVX groups (P<0.05). Isolated pial artery (pressure myography) vasoconstriction to neuropeptide Y was greatest in the AB‐OVX group (P<0.05), and vasodilation to the Ca(2+)‐activated potassium channel α‐subunit agonist NS‐1619 was impaired in both AB groups (P<0.05). The ratio of phosphorylated endothelial nitric oxide synthase:total endothelial nitric oxide synthase was depressed and Ca(2+)‐activated potassium channel α‐subunit protein was increased in AB groups (P<0.05). CONCLUSIONS: Mechanistically, impaired cerebral blood flow control in experimental heart failure may be the result of heightened neuropeptide Y–induced vasoconstriction along with reduced vasodilation associated with decreased Ca(2+)‐activated potassium channel function and impaired nitric oxide signaling, the effects of which are exacerbated in the absence of female sex hormones.