Yang Yanrong, Chen Hua, Liu Qibing, Niu Yang, Mao Chunyang, Wang Rui
College of Pharmaceutical Science and Key Laboratory of Ministry of Education in Protection and Utilization of Medicinal Resources of Liupanshan Area, Ningxia Medical University, Yinchuan, Ningxia, China.
Engineering Research Center of Tropical Medicine Innovation and Translational of Hainan and Department of Pharmacy, The First Affiliated Hospital of Hainan Medical University, Haikou, Hainan, China.
Front Aging Neurosci. 2025 Jul 16;17:1623050. doi: 10.3389/fnagi.2025.1623050. eCollection 2025.
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. Disruptions in cerebral hemodynamics 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.
血管性痴呆（VaD）是第二常见的痴呆亚型，仅次于阿尔茨海默病（AD）。神经功能和脑内环境稳定的维持严重依赖于错综复杂的脑血管网络中精确调节的血流。脑血流动力学的破坏可能损害神经血管内环境稳定，从而引发以氧化应激、神经炎症和神经元变性为特征的病理生理级联反应。新出现的证据表明，脑血管调节异常和神经血管耦合（NVC）受损是VaD的主要致病机制，强调了阐明它们复杂相互作用的必要性。脑血管内皮细胞表现出显著的异质性，既作为血脑屏障（BBB）的结构成分，又作为NVC的功能调节因子发挥双重作用。此外，位于毛细血管内皮细胞无腔侧的周细胞通过对微血管张力的收缩调节在血流动力学调节中发挥关键作用，同时通过动态旁分泌信号维持BBB的完整性。本研究在神经血管单元（NVU）框架内研究脑血管内皮-神经元相互作用，分析它们在认知功能障碍修复中的双向调节机制和治疗潜力。VaD的病理生理进展通过多种相互依赖的途径表现出来，包括脑灌注不足、氧化应激级联反应、神经炎症反应、线粒体调节异常和电解质内环境紊乱。通过三个干预轴：（1）BBB强化策略；（2）脑血流动力学优化和NVC增强；（3）整合内皮特异性分子靶点的纳米治疗平台，我们系统地评估了以内皮细胞为中心的治疗模式。这种多模式方法为VaD管理提出了新的机制见解和临床转化框架。
