Disruption of Vitamin D Signaling Impairs Adaptation of Cerebrocortical Microcirculation to Carotid Artery Occlusion in Hyperandrogenic Female Mice

Abstract

Vitamin D deficiency contributes to the pathogenesis of age-related cerebrovascular diseases, including ischemic stroke. Sex hormonal status may also influence the prevalence of these disorders, indicated by a heightened vulnerability among postmenopausal and hyperandrogenic women. To investigate the potential interaction between sex steroids and disrupted vitamin D signaling in the cerebral microcirculation, we examined the cerebrovascular adaptation to unilateral carotid artery occlusion (CAO) in intact, ovariectomized, and hyperandrogenic female mice with normal or functionally inactive vitamin D receptor (VDR). We also analyzed the morphology of leptomeningeal anastomoses, which play a significant role in the compensation. Ablation of VDR by itself did not impact the cerebrocortical adaptation to CAO despite the reduced number of pial collaterals. While ovariectomy did not undermine compensatory mechanisms following CAO, androgen excess combined with VDR inactivity resulted in prolonged hypoperfusion in the cerebral cortex ipsilateral to the occlusion. These findings suggest that the cerebrovascular consequences of disrupted VDR signaling are less pronounced in females, providing a level of protection even after ovariectomy. Conversely, even short-term androgen excess with lacking VDR signaling may lead to unfavorable outcomes of ischemic stroke, highlighting the complex interplay between sex steroids and vitamin D in terms of cerebrovascular diseases.

NO Deficiency Compromises Inter- and Intrahemispheric Blood Flow Adaptation to Unilateral Carotid Artery Occlusion

“…The availability of nitric oxide (NO), a potent vasodilator produced by endothelial cells and neurons, plays a critical role in regulating CBF and maintaining cerebrovascular homeostasis [2,[33][34][35][36][37][38][39][40][41][42]. Impaired bioavailability of NO, associated with advanced aging and comorbidities such as hypertension, diabetes mellitus, vitamin D deficiency, and cardiovascular disease [43][44][45], is likely to contribute to compromised CBF homeostasis in older patients at risk for VCI. Understanding the combined impact of CAS and these comorbidities on the compensatory mechanisms and adaptive responses of the cerebral microcirculation is crucial in elucidating the clinical consequences of CAS.…”