Ablation of Vitamin D Signaling Compromises Cerebrovascular Adaptation to Carotid Artery Occlusion in Mice

Abstract

Vitamin D insufficiency has been associated with increased incidence and severity of cerebrovascular disorders. We analyzed the impact of impaired vitamin D signaling on the anatomical and functional aspects of cerebrovascular adaptation to unilateral carotid artery occlusion (CAO), a common consequence of atherosclerosis and cause of ischemic stroke. Cerebrocortical blood flow (CoBF) showed a significantly increased drop and delayed recovery after CAO in mice carrying a functionally inactive vitamin D receptor (VDR) with the most sustained perfusion deficit in the temporal cortex. To identify the cause(s) for this altered adaptation, the extent of compensatory blood flow increase in the contralateral carotid artery and the morphology of pial collaterals between the anterior and middle cerebral arteries were determined. Whereas VDR deficiency had no significant influence on the contralateral carotid arterial blood flow increase, it was associated with decreased number and increased tortuosity of pial anastomoses resulting in unfavorable changes of the intracranial collateral circulation. These results indicate that VDR deficiency compromises the cerebrovascular adaptation to CAO with the most sustained consequences in the temporal cortex. The dysregulation can be attributed to the altered development and function of pial collateral circulation whereas extracranial vessels may not be impaired.

Role of Vitamin D Deficiency in the Pathogenesis of Cardiovascular and Cerebrovascular Diseases

“…The available preclinical evidence suggest that VDD may interfere with autoregulation of cerebral blood flow [ 219 , 220 ]. This concept is also supported by the findings that VDD impairs both cerebrovascular morphology and function in rodents [ 110 , 219 , 220 , 221 ]. Among others, VDD induces hypertrophic remodeling, resulting from enhanced vascular smooth muscle cell proliferation in the cerebral arteries of male rats [ 221 ].…”

“…VitD also might impact the pathogenesis of cardiovascular diseases, including CAD directly. In rodent models of VDD, morphological remodeling and altered vasoreactivity of intramural coronary arteries have been reported [ 109 , 110 , 111 ]. The aforementioned alterations in the coronary arterioles may impair the coronary circulation, therefore increasing the risk for cardiovascular disease.…”

“…These alterations may result from enhanced vasoconstrictor prostanoid production, due to increased COX-2 expression and from decreased eNOS expression, leading to diminished NO production in cerebral vessels ( Figure 3 ) [ 221 , 222 , 223 , 224 ]. Functional impairment and pathological remodeling of the cerebral vessels in VDD compromises cerebrovascular adaptation to ischemic events [ 110 ], increasing the risk for ischemic stroke and/or worsening its outcome [ 225 , 226 , 227 , 228 , 229 , 230 ]. Interestingly, in preclinical models, females appear to be better protected from the cerebrovascular effects of VDD than males; therefore, sex differences should be considered in clinical studies investigating the cerebrovascular manifestations of VDD, as well [ 219 , 220 ].…”

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

“…As the initial step of the experimental protocol, atipamezole (1 µg/g ip. ; Sigma-Aldrich, St. Louis, MO, USA) was administered as an antidote to counteract the blood pressure-lowering effects of xylazine [55,68]. Following the attainment of stabilized blood pressure, N-nitro-L-arginine methyl ester (L-NAME 10 mg/kg i.p.…”

Vitamin D Deficiency and Gender Alter Vasoconstrictor and Vasodilator Reactivity in Rat Carotid Artery

“…Vitamin D deficiency is a potential risk factor for several cardio-cerebrovascular diseases and events, including stroke [ 5 ]. Impaired vitamin D signaling in functionally inactive vitamin D receptor mutant male mice caused compromised cerebrovascular adaptation to unilateral carotid artery occlusion [ 6 ]. Four-week-long vitamin D deficient and vitamin D toxic (25(OH)D > 200 ng/mL or > 500 nmol/L [ 2 ]) diets resulted in significantly decreased carotid artery diameter and significantly enhanced wall thickness in male rats [ 7 ].…”