Elucidating Molecular Pathogenesis and Developing Targeted Therapeutic Interventions for Cerebrovascular Endothelial Cell-Mediated Vascular Dementia

Yanrong Yang¹Hua Chen²Qibing Liu³Yang Niu^4*Rui WANG^1*

• ¹Department of Pharmaceutical Analysis, School of Pharmacy, Ningxia Medical University, Yinchuan, China
• ²Key Laboratory of Ministry of Education in Protection and Utilization of Medicinal Resources of Liupanshan Area, Ningxia Medical University, Yinchuan 750004, Ningxia, China, Yinchuan , Ningxia, China, China
• ³The First Aaffiliated Hospital of Hainan Medical University, Haikou 570100, Hainan, China, Haikou , Hainan, China, China
• ⁴2. Key Laboratory of Ministry of Education in Modernization of Minority Medicine, Ningxia medical University, Yinchuan 750004, Ningxia, China, Yinchuan , Ningxia, China, China

Abstract：Vascular dementia (VaD) ranks as the second most prevalent subtype of dementia, surpassed only by Alzheimer's disease (AD). The maintenance of neurological function and cerebral homeostasis critically depends on precisely regulated blood flow within the intricately organized cerebrovascular network.may impair neurovascular homeostasis, thereby inducing pathophysiological cascades characterized by oxidative stress, neuroinflammation, and neuronal degeneration. Emerging evidence identifies cerebrovascular dysregulation and impaired neurovascular coupling (NVC) as primary pathogenic mechanisms underlying VaD, emphasizing the necessity to elucidate their complex interplay. Cerebrovascular endothelial cells exhibit remarkable heterogeneity, serving dual roles as both architectural components of the blood-brain barrier (BBB) and functional regulators of NVC. Furthermore, pericytes residing abluminal on capillary endothelia demonstrate critical involvement in hemodynamic modulation through contractile regulation of microvascular tone, while concurrently maintaining BBB integrity through dynamic paracrine signaling. This study examines cerebrovascular endothelial-neuronal interactions within the neurovascular unit (NVU) framework, analyzing their bidirectional regulatory mechanisms and therapeutic potential in cognitive dysfunction remediation. The pathophysiological progression of VaD manifests through multiple interdependent pathways, including cerebral hypoperfusion, oxidative stress cascades, neuroinflammatory responses, mitochondrial dysregulation, and electrolyte homeostasis perturbations. Through three interventional axes: (1) BBB fortification strategies; (2) cerebral hemodynamic optimization and NVC enhancement; (3) nanotherapeutic platforms integrating endothelial-specific molecular targets we systematically evaluate endothelial-centric therapeutic paradigms. This multi-modal approach proposes novel mechanistic insights and clinical translation frameworks for VaD management.