VaD is frequently associated with damage to cerebrovascular endothelial cells (Goncharov et al., 2024). The concept of the neurovascular unit (NVU) is introduced to highlight the intricate relationship between brain cells and the cerebrovascular system (Iadecola, 2017). The NVU comprises neurons, glial cells, pericytes, endothelial cells, and vascular smooth muscle cells. As shown in Figure 1. From a functional perspective, the dynamic interactions among these cellular components contribute to the precise regulation of CBF, the maintenance of blood–brain barrier (BBB) integrity, the fulfillment of metabolic demands, and the facilitation of brain development, nutrition, and repair. Cerebrovascular endothelial cells enable the selective passage of nutrients and molecules essential for brain function while preventing the ingress of neurotoxic substances (Alkhalifa et al., 2023; Montagne et al., 2017). The NVU ensures the proper functioning of neuronal circuits by regulating BBB permeability, modulating CBF, and preserving the stability of the neuronal microenvironment (Smith et al., 2022). Consequently, the heterogeneity of cerebrovascular endothelial cells not only constitutes a major structural component of the BBB but also serves as a critical functional link in neural coupling activity.

The cerebrovascular system supplies energy for cerebral neural activity, and fluctuations in neural activity elicit corresponding alterations in regional CBF within seconds, a mechanism formally termed neurovascular coupling (NVC). The precise interdependency between neuronal activity and CBF substantiates the brain’s minimal metabolic reserves and the imperative for rapid oxygen and glucose mobilization to activated cerebral regions CBF modulation is mediated through NVC mechanisms orchestrated by specialized NVU (Banerjee and Banerjee, 2024). Compromised NVC functionality may precipitate cerebral microcirculatory ischemia and hypoxia, impair local neuronal signal propagation, exacerbate cerebral small vessel pathology, and ultimately manifest as cognitive impairment or dementia (Chow et al., 2020). NVC constitutes a fundamental regulatory framework for cerebral hemodynamics. Age-related deterioration of this mechanism may constitute a pathogenic pathway toward cognitive decline (Tarantini et al., 2019). Vascular endothelial cells, recognized as key effectors in hemodynamic regulation through chemical and mechanical transduction, have emerged as critical components in NVC research (Harraz et al., 2022).

Cerebral hypoxia, either as global hypoxia or as focal cerebrovascular accident or stroke, is a severe neurological disorder with heterogeneous characteristics and multiple etiologies, which represents the second cause of death and the disease with the greatest sequelae of disability in the world. Although the hippocampus demonstrates heightened susceptibility to ischemic–hypoxic conditions, the vascular endothelial growth factor (VEGF) manifests enhanced resistance to hypoxic–ischemic neuronal injury. Quantification revealed significantly elevated densities of VEGF-immunopositivity cells in the hypoxic cerebral cortex relative to hippocampal regions (Jun et al., 2020). Compelling evidence indicates that chronic cerebral hypoperfusion (CCH) serves as a pivotal pathophysiological mechanism underlying the initiation and evolution of VaD (Chen et al., 2024). Prolonged ischemic–hypoxic stress induces degradation of BBB tight junction proteins, elevates microvascular permeability, and stimulates concomitant upregulation of pro-angiogenic mediators including VEGF-A within cerebral endothelial cells and pericytes. Experimental administration of minocycline in rodent models has been demonstrated to attenuate BBB compromise, ameliorate white matter pathology, and potentiate neovascularization processes (Yang et al., 2018). Hypoxia-inducible factor (HIF)-mediated signaling operates as an adaptive cytoprotective mechanism activated by hypoxia, ischemia, and related pathological states (Yang et al., 2013). Under hypoxic conditions, HIF-1α coordinates osteogenic and angiogenic processes through modulation of the VEGF/AKT/mTOR signaling axis, while simultaneously facilitating the recruitment of bone marrow-derived angiogenic progenitor cells to ischemic microenvironments (Song et al., 2023). Notably, HIF-1α demonstrates neuroprotective efficacy against acute ischemic and hypoxia-associated vascular dementia via coordinated activation of PI3K/AKT/mTOR and MAPK cascades (Abdel-Latif et al., 2018). Pharmacological interventions employing berberine have been shown to suppress pathological angiogenesis and cellular apoptosis through selective inhibition of the HIF-1α/VEGF/DLL-4/Notch-1 signaling nexus (Ai et al., 2022). Emerging evidence suggests that vascular endothelial cells exert neuroprotective influences during post-hypoxic neuronal pathophysiology, thereby positioning enhanced NVC dynamics and targeted vascular remodeling as promising therapeutic modalities for cerebral injury mitigation (Wu et al., 2016). Ischemia-induced degradation of the microvascular matrix architecture correlates temporally with microglial cathepsin L secretion during lesion progression. Strategic targeting of cathepsin L-mediated proteolytic activity and its synergistic interplay with matrix metalloproteinase (MMP) systems may offer novel approaches for attenuating microvascular compromise and hemorrhagic complications (Gu et al., 2015).

Oxidative stress represents a pathological process characterized by the excessive accumulation of reactive oxygen species (ROS) and free radicals within the body, which can induce structural damage to cellular components. Naringenin mitigates oxidative stress in the hippocampus of vascular dementia rats by suppressing ROS production, reducing malondialdehyde (MDA) levels, and enhancing the enzymatic activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in the hippocampus. Furthermore, naringenin decreases the levels of pro-inflammatory cytokines while elevating those of anti-inflammatory cytokines in the hippocampus of 2-VO model rats, thereby alleviating hippocampal inflammatory responses in VaD model rats (Zhang et al., 2022). Oxidative stress may serve as a critical risk factor for Amyloid-beta (Aβ) deposition in the cerebrovascular system by initiating the amyloidogenic pathway of endothelial amyloid precursor protein (APP) processing. The increased β-secretase activity following oxidative stress exposure could potentially be mediated through the phosphorylation of p42/44 MAPK (Muche et al., 2017). Long-term administration of CU06-1004, a therapeutic agent targeting endothelial dysfunction through suppression of vascular leakage and enhancement of vascular integrity under ischemia–reperfusion conditions, markedly alleviated age-associated cerebral microvascular rarefaction and cerebrovascular senescence in aged murine models. Concurrent behavioral assessments revealed significant amelioration of motor coordination and cognitive performance in senescence-accelerated mice subjected to sustained CU06-1004 intervention (Kim et al., 2023). The neuroprotective efficacy of glycyrrhizin (GA) in rodent models of VaD was mechanistically linked to its dual capacity for attenuating oxidative stress and modulating voltage-gated Na⁺ channel activity within hippocampal CA1 pyramidal neurons. Collectively, these investigations furnish compelling preclinical evidence endorsing the therapeutic potential of glycyrrhizin in addressing cognitive impairments secondary to neurodegenerative disorders, cerebrovascular accidents, or neurotrauma (Guo et al., 2016). Beyond its chrono biotic functions, melatonin demonstrates substantial free radical-scavenging capabilities and exerts neuroprotection effects via mitigation of cerebral oxidative stress and suppression of neuroinflammatory cascades (Delgado-Lara et al., 2020). Notably, nicotinamide mononucleotide administration effectively enhances microvascular endothelial homeostasis and reinstates nitric oxide-dependent NVC mechanisms in aged murine subjects (Tarantini et al., 2019).

Neuroinflammation represents an immune cascade orchestrated by glial cells within the central nervous system, the principal site of innate immunity. CCH-induced persistent ischemia and hypoxia trigger excessive neuroinflammatory activation, culminating in cellular apoptosis, BBB compromise, and associated pathological manifestations that accelerate the pathogenesis of VaD (Tian et al., 2022). Notably, miR-193b-3p and miR-152-3p inhibition nullified tilianin-mediated cognitive enhancement achieved through p38-MAPK/NF-κB-p65 and Bcl2/Bax/Caspase-3/PARP pathway activation in 2-VO rat models. Crucially, calmodulin and Calmodulin-Stimulated Protein Kinase II (CaMKII) overexpression counteracted the synergistic therapeutic effects of tilianin and miR-193b-3p/miR-152-3p against ischemic injury by exacerbating inflammatory cascades and apoptosis regulatory mechanisms (Sun et al., 2023). Experimental data further demonstrate that XSB ameliorates BCAS-induced cognitive impairment via multimodal mechanisms including cerebral perfusion modulation, white matter lesion attenuation, glial cell activation suppression, and neuroinflammatory resolution. Gastrodin exerted neuroprotective effects in rats with neuroinflammation by impacting the TLR4-NF-κB-NLRP3 pathway. Therefore, gastrodin may be a potential therapeutic agent for neuroinflammation-induced cognitive dysfunction (Luo et al., 2024). By preventing brain endothelial injury, which preserves BBB integrity, reduces neuroinflammatory responses, and maintains the functional competence of the NVU, thrombin inhibition or targeting its downstream signaling effectors could offer a viable therapeutic approach for mitigating diabetes-associated dementia (Vittal Rao et al., 2021). Crucially, NF-κB signaling emerges as a central mediator in this pathological cascade (Xiao et al., 2024). The systemic inflammatory response exhibits dynamic characteristics, with cytokine profiles demonstrating temporal and severity-dependent variations in VaD. Age-related oxidative stress, persistent DNA damage accumulation, and compromised DNA repair mechanisms collectively jeopardize both neuronal genomic stability and the functional integrity of neurovascular components including endothelial cells, astrocytes, and pericytes (Li et al., 2019). Endothelial colony forming cells (ECFCs), a specialized subset of endothelial progenitors, play indispensable roles in vascular homeostasis, regenerative repair, and neovascularization through their clonal expansion potential. The aging process compromises ECFCs functionality via multifactorial pathways encompassing oxidative damage, sustained low-grade inflammation, and cellular senescence, ultimately manifesting as diminished vascular regenerative capacity and compromised neurovascular compliance. These progenitor cells directly modulate critical cerebrovascular functions such as NVC dynamics, BBB maintenance, and angiogenic processes. Progressive age-dependent depletion of ECFCs populations, coupled with functional deterioration, induces cerebral microvascular attrition and hemodynamic insufficiency, synergistically accelerating cognitive impairment progression (Negri et al., 2025).

The pathogenesis of VaD is highly complex, involving intricate interactions among various influencing factors. The “hypoxia-oxidative stress-inflammation” cascade forms a detrimental feedback loop, wherein the activation of one factor can trigger the others, ultimately resulting in progressive brain dysfunction during the course of vascular dementia. As depicted in Figure 3, hypoxia, oxidative stress, neuroinflammation, and apoptosis compromise the integrity of tight junctions, thereby inducing BBB disruption and subsequent brain injury.

Substantial evidence has established the involvement of mitochondrial dysfunction in neurodegenerative disorders (Khacho et al., 2019; Wallace, 2005). Mitochondrial impairment constitutes a pivotal pathogenic mechanism underlying vascular dementia. Experimental findings indicate that gastrodin ameliorates CCH-induced mitochondrial dysfunction in VaD through modulation of the SIRT3/TFAM signaling axis, presenting a natural therapeutic target for dementia reversal (Chen et al., 2024). As demonstrated in Figure 4, integrated in vivo and in vitro investigations revealed that nicotinamide adenine dinucleotide (NAD⁺) administration attenuated CCH-induced cognitive impairment by suppressing ROS generation through SIRT1/PGC-1α pathway activation (Zhao et al., 2021). The AKT/mTOR signaling cascade, widely recognized as a canonical regulator of cellular homeostasis and bioenergetic metabolism, has emerged as a promising therapeutic focus for neurodegenerative disease intervention (Huang J. et al., 2022; Stiles, 2009). The AKT/mTOR signaling pathway has been demonstrated to play a pivotal regulatory role in mitochondrial homeostasis. Pharmacological modulation of S1PR2 substantially attenuates AKT/mTOR pathway activation, consequently suppressing Aβ_25-35-induced autophagic flux in cellular models and ameliorating cognitive deficits (Fan et al., 2015). This neuroprotective mechanism may be mediated through the diminution of mitochondrial Ca²⁺ overload, which critically compromises mitochondrial bioenergetics (Zhou and Tan, 2020). Sirtuin 3 (SIRT3), a mitochondrial-localized NAD⁺-dependent deacetylase, serves as a master regulator of mitochondrial integrity through its governance of ATP biosynthesis, redox balance maintenance, and modulation of apoptotic or proliferative pathways. Emerging evidence highlights the pathogenic implications of SIRT3 dysregulation in neurodegenerative disorders. Therapeutic targeting of TDP43-driven Glycogen synthase kinase-3β (GSK3β) activation to restore ER-mitochondrial cross-talk represents a promising strategy with potential translational applications (Matsuyama et al., 2020). Free radicals originating from mitochondrial dysfunction contribute to homeostatic imbalance and lipid peroxidation. NOX4 exacerbates mitochondrial metabolic impairments and diminishes intracellular iron concentrations in patients via oxidative stress-mediated lipid peroxidation (Park et al., 2021). The augmentation of ROS generation through mitochondrial pathways, coupled with the activation of mitochondrial oxidative stress, suppression of ATP biosynthesis, and elevation of glycolytic activity, collectively inflict damage upon mitochondrial DNA. These mechanisms ultimately attenuate mitochondrial dysfunction and vascular inflammation within cerebral microvascular endothelial cells (Nyunt et al., 2019). In the context of traumatic brain injury, epileptic seizures and widespread cortical depolarization may potentiate secondary cerebral damage, precipitating mitochondrial dysfunction, compromised cortical perfusion, and neurobehavioral impairments, mitochondrial dysfunction underlies impaired NVC following traumatic brain injury (van Hameren et al., 2023).

Metal ion homeostasis plays a pivotal role in preserving normal physiological functions of organisms. Experimental evidence indicates that amorphous selenium substantially enhances learning and memory capacity in rodent models of VaD, promotes restoration of cerebral arterial hemodynamics, facilitates morphological recovery of hippocampal CA1 pyramidal neurons through dendritic remodeling, attenuates oxidative stress biomarkers, upregulates CaMKII protein expression, and effectively modulates intracellular calcium homeostasis (Zhu et al., 2023). In this investigation, we developed a novel metal-chelating compound that demonstrated potent inhibitory effects on Tau phosphorylation via iron ion sequestration both in vitro and in vivo, effectively alleviating pathological manifestations. These discoveries elucidate previously unrecognized mechanisms by which Tau protein aggregation mediates memory impairment (Zuo et al., 2024). Dietary exposure to elevated aluminum concentrations whether through food additives or contaminated water sources may exacerbate susceptibility to cognitive decline, with aluminum ions potentially functioning as synergistic participants in neurodegenerative cascades culminating in cerebral dementia (Solfrizzi et al., 2006).

Elevated intracellular iron ion concentrations induce substantial generation of ROS radicals, exacerbating oxidative stress and consequently precipitating cellular damage and apoptosis. Iron deposition in hippocampus in model groups which accompanied the decline of learning and memory function, iron deposition increased AMPK/autophagy pathway associated molecules in the hippocampus and promoted neuronal apoptosis, which might be a new pathogenesis in VaD (Huo et al., 2019). Copper ranks as the third most prevalent trace element in the cerebral environment, whereas zinc–an essential micronutrient released via synaptic vesicles during neuronal activation–serves a pivotal regulatory function in neural signal processing. Synaptic Cu²⁺ demonstrates synergistic coordination with Zn²⁺, potentiating neuronal degeneration and substantially contributing to the etiological mechanisms underlying VaD (Tanaka and Kawahara, 2017). While Mn²⁺ and Ni²⁺ exhibit modulatory effects on Zn²⁺-mediated neurotoxicity, their pathogenic influence remains notably diminished compared to Cu²⁺. Subthreshold Cu concentrations paradoxically amplify Zn-associated neurotoxic manifestations. Under pathological states including transient ischemic episodes, disrupted copper ion homeostasis culminates in aberrant Cu²⁺ accumulation, thereby facilitating excessive Zn²⁺ exocytosis into synaptic spaces and subsequent neuronal mortality (Kawahara et al., 2024).