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.

Carotid artery stenosis (CAS) affects approximately 5–7.5% of older adults and is recognized as a significant risk factor for vascular cognitive impairment (VCI). The impact of CAS on cerebral blood flow (CBF) within the ipsilateral hemisphere relies on the adaptive capabilities of the cerebral microcirculation. In this study, we aimed to test the hypothesis that the impaired availability of nitric oxide (NO) compromises CBF homeostasis after unilateral carotid artery occlusion (CAO). To investigate this, three mouse models exhibiting compromised production of NO were tested: NOS1 knockout, NOS1/3 double knockout, and mice treated with the NO synthesis inhibitor L-NAME. Regional CBF changes following CAO were evaluated using laser-speckle contrast imaging (LSCI). Our findings demonstrated that NOS1 knockout, NOS1/3 double knockout, and L-NAME-treated mice exhibited impaired CBF adaptation to CAO. Furthermore, genetic deficiency of one or two NO synthase isoforms increased the tortuosity of pial collaterals connecting the frontoparietal and temporal regions. In conclusion, our study highlights the significant contribution of NO production to the functional adaptation of cerebrocortical microcirculation to unilateral CAO. We propose that impaired bioavailability of NO contributes to the impaired CBF homeostasis by altering inter- and intrahemispheric blood flow redistribution after unilateral disruption of carotid artery flow.

Age-related dysfunction of the central nervous system, including cognitive impairment and visual disorders, is a major concern for the aging population, affecting health span and quality of life. Age-related vascular dysfunction in the central nervous system includes an increase in blood-brain or blood-retina barrier permeability, an increase in vascular fragility, and impaired neurovascular coupling, contributing to cognitive impairment and vision loss. While these pathologies occur in the brain and eye with age, gaps remain in our understanding of the underlying cellular mechanisms. During the process of endothelial-to-mesenchymal transition (EndMT), endothelial cells lose their characteristic endothelial phenotypes, which are critical for vascular function, such as barrier integrity, and transition to a mesenchymal-like phenotype. EndMT is triggered by many age-related stimuli and is involved in the progression of many age-related diseases (eg, atherosclerosis, cardiovascular disease, etc). Here, we review what is known about the role of EndMT in vascular fragility in the aging brain and eye, explore the mechanistic links between endothelial cell transdifferentiation and age-associated vascular pathologies of the central nervous system, and identify potential therapeutic targets ripe for future exploration with the goal of preserving vascular function with aging by regulating EndMT. SIGNIFICANCE STATEMENT: Endothelial-to-mesenchymal transition is a key form of cellular plasticity that leads to disrupted barrier function and vascular disorders. Here, we evaluate what is known about this process in the brain, highlight potential targetable mechanisms to block it, and identify areas where further research is needed.

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.

Chemotherapy-induced cognitive impairment, commonly referred to as chemobrain, represents a major and increasingly recognized long-term consequence of cancer treatment, contributing to persistent cognitive decline in a substantial proportion of cancer survivors. While traditionally attributed to direct neuronal toxicity, accumulating evidence suggests that many chemotherapeutic agents exert their central nervous system effects through indirect, pharmacologically mediated mechanisms. Notably, most widely used chemotherapies have limited penetration across the intact blood–brain barrier, prompting a re-evaluation of how systemic cytotoxic agents disrupt brain function. This mini-review advances a neurovascular framework for understanding chemotherapy-induced chemobrain, emphasizing injury to the cerebral microvasculature as a key pathogenic axis. We synthesize emerging preclinical and translational data indicating that chemotherapeutic agents target the cerebrovascular endothelium, leading to persistent alterations in blood–brain barrier integrity, microvascular density, cerebral blood flow regulation, and neurovascular coupling. These changes create a permissive environment for chronic neuroinflammation, metabolic stress, and impaired neuronal support, ultimately manifesting as cognitive decline. By framing chemobrain as a consequence of neurovascular dysfunction driven by pharmacological off-target effects, this review highlights novel opportunities for therapeutic intervention. Targeting vascular injury pathways, endothelial dysfunction, and maladaptive stress responses may offer promising strategies to prevent or mitigate cognitive decline in cancer survivors, shifting the focus from symptomatic management toward mechanism-based neuroprotection.