Progress in pathological mechanisms and targeted strategies for endothelial dysfunction-mediated cerebral small vessel disease

<?A3B2 tlsb=.01w?>Cerebral small vessel disease (CSVD) encompasses a spectrum of disorders affecting the brain′s microvasculature, including small arteries, arterioles, capillaries, and venules. As a highly prevalent condition in aging populations and a major contributor to vascular cognitive impairment, stroke, and dementia, its clinical management remains predominantly supportive, focusing on controlling conventional vascular risk factors without addressing underlying core pathologies. Emerging evidence firmly establishes endothelial dysfunction as the pivotal initiating and perpetuating factor in CSVD. This dysfunction manifests as impaired vasoreactivity, blood-brain barrier (BBB) disruption, a pro-inflammatory and pro-thrombotic endothelial phenotype, and compromised neurovascular coupling, thereby serving as the critical mechanistic link between systemic risk factors and end-organ brain injury. This review provides a systematic synthesis of the current understanding of CSVD. We first outline its heterogeneous clinical presentations, from subtle executive deficits to overt dementia and gait disturbances, and detail the established neuroimaging hallmarks defined by STRIVE criteria, such as white matter hyperintensities, lacunes, and cerebral microbleeds. The discussion extends to promising fluid biomarkers reflecting endothelial activation, BBB leakage, and neuroinflammation. Subsequently, we delineate the essential physiological roles of cerebrovascular endothelial cells, emphasizing their central functions in orchestrating neurovascular coupling for dynamic cerebral blood flow control, in forming and maintaining the selective BBB, and in sustaining local anticoagulant and anti-inflammatory homeostasis. A central focus of this review is a detailed analysis of how endothelial dysfunction drives core pathological processes in CSVD: (1) structural vascular remodeling, evolving from adaptive wall thickening to maladaptive arteriolosclerosis and lumen stenosis; (2) hemodynamic failure, characterized by impaired cerebral autoregulation and vasoreactivity, leading to chronic hypoperfusion, capillary rarefaction, and heightened susceptibility to microhemorrhages; (3) neurovascular unit disintegration, wherein BBB breakdown precipitates vasogenic edema, neuroinflammation, excitotoxicity, and impaired clearance of metabolic waste via the glymphatic system; and (4) compromised repair mechanisms, resulting from diminished secretion of neurotrophic factors and deficient angiogenic responses. We then critically evaluate emerging therapeutic strategies aimed at restoring endothelial function. Pharmacological approaches are categorized into agents designed to enhance endothelial vasodilation, suppress endothelial inflammation, reduce oxidative stress, and bolster BBB integrity. Innovative avenues, including endothelial progenitor cell transplantation and microRNA-based therapies, are also highlighted. Additionally, we summarize current methods for assessing endothelial dysfunction in CSVD, covering circulating biomarkers, advanced neuroimaging techniques, and retinal vascular analysis. In conclusion, while targeting endothelial dysfunction presents a highly promising strategy for CSVD treatment, significant translational challenges persist. These include the pathological heterogeneity of CSVD subtypes, the absence of specific biomarkers for patient stratification, the lack of sensitive and direct clinical trial endpoints, and the difficulty in achieving brain microvascular-selective drug delivery. Future research must prioritize the integration of multi-omics data to define endothelio-centric disease endotypes, the development of novel targeted therapeutics and delivery systems, the validation of composite dynamic endpoints, and the exploration of non-pharmacological interventions for early-stage disease modulation. A deeper mechanistic understanding coupled with advanced therapeutic targeting holds considerable potential to modify the disease trajectory and improve clinical outcomes for patients with CSVD. <alternatives id="alt1"> </alternatives>