Epidemiological studies reveal a significant burden of cSVD, particularly in low- and middle-income countries (LMICs). While there is growing recognition of the impact of cSVD on global health, specific data on individual stroke subtypes—such as lacunar stroke—remains relatively limited, especially in these regions (4). A recent review by Lam et al. (5) highlights the high prevalence of imaging features associated with cSVD in LMICs. The study reported that between 20.5% and 58.4% of individuals in community, stroke, and dementia groups exhibited moderate-to-severe white WMH, which is a key radiological marker of cSVD (5). These findings indicate that cSVD is a widespread concern, even in populations with limited healthcare resources (6). This data from LMICs aligns with findings from high-income countries, where WMH and other radiological features of cSVD are similarly common (5). However, the need for more comprehensive studies in LMICs is crucial. A deeper understanding of the global prevalence of cSVD and its regional variations would help in tailoring preventive strategies and health policies to address the burden more effectively. Moreover, certain non-western populations, particularly in Asia, show an even higher burden of cSVD, which is often linked to an increased risk of dementia (7). In these regions, the presence of cSVD lesions appears to have a synergistic effect with Alzheimer’s disease (AD), lowering the threshold for the development of clinically significant dementia (8). This means that individuals with cSVD may experience an accelerated decline in cognitive function when combined with AD pathology, leading to earlier and more severe dementia onset.

cSVD are primarily identified through brain MRI, which reveals characteristic features such as WMHs, small subcortical infarcts or lacunes, visible perivascular spaces (PVSs), microbleeds, intracerebral hemorrhage (ICH), and brain atrophy (9). However, conventional MRI may only capture the more obvious lesions, missing subtle changes that could be present in other areas of the brain (10). More advanced imaging techniques like diffusion tensor imaging (DTI) are more sensitive and can detect alterations in diffusion properties in regions that appear normal on traditional MRI scans (11). Clinically, cSVD often presents with stroke due to small subcortical infarcts, motor impairments, balance problems, and cognitive decline, particularly affecting executive function and processing speed (1). Additionally, neuropsychiatric symptoms such as apathy, fatigue, depression, and delirium are increasingly recognized as key manifestations (12). The disease can range from asymptomatic cases, where brain lesions are incidentally found on MRI in individuals over 50, to severe cases leading to disability and dementia (13). The progression of cSVD is typically gradual and silent, with many individuals showing no symptoms until the condition becomes clinically significant. This slow progression is also observed in monogenic forms of cSVD, which are often indistinguishable from the sporadic form of the disease.

Endothelial cells (ECs) dysfunction refers to the impaired functioning of the endothelial cells lining blood vessels, which can have significant implications for vascular health and the organs they serve (17). Under normal conditions, endothelial cells help regulate blood flow, act as a selective barrier, and respond to signals involved in inflammatory processes. In the brain, these cells form the BBB, characterized by tight junctions between the cells that protect the brain from harmful substances while allowing the selective passage of molecules into the brain tissue (18).

When endothelial cells become dysfunctional, they lose these protective functions and may acquire new, harmful characteristics. A hallmark of EC dysfunction is a reduced ability to produce and release nitric oxide, which normally helps dilate blood vessels (19). This results in impaired vascular responses. Although endothelial dysfunction and vascular dysfunction are related, they are distinct processes. Vascular dysfunction can also arise independently of ECs, originating from pericytes or smooth muscle cells. Additionally, endothelial activation, characterized by the upregulation of adhesion molecules like VCAM-1 (20), ICAM-1 (21), and E-selectin (22), often occurs in response to inflammation and is linked to endothelial dysfunction but is considered a separate phenomenon.

ECs play a crucial role in the brain’s vascular system, extending beyond their function as the inner lining of blood vessels. In the brain, ECs are essential for maintaining the integrity of the BBB, regulating molecular transport, and facilitating processes like blood clotting and neurovascular coupling—matching blood flow to neural activity. They also interact with brain cells on their albuminal side, further influencing brain function. When ECs become dysfunctional, these processes are disrupted, contributing to the development and progression of cSVD, a condition linked to various subtypes based on its cause and pathology (23).

In particular, endothelial dysfunction is increasingly recognized as a key factor in the mechanisms driving parenchymal changes in cSVD. Dysfunctional ECs impair the BBB and neurovascular coupling, leading to changes in white matter (WM). This disruption is thought to occur through altered cellular interactions and secretions from ECs. At the molecular level, EC dysfunction is marked by changes in the expression of various proteins and markers that can serve as indicators of disease progression. Animal models of cSVD have helped identify these molecular signatures, providing insight into how EC dysfunction contributes to WM damage.

MMP-2 and MMP-9 are elevated in cSVD and play dual pathogenic roles (40, 41). These enzymes degrade tight junction proteins (claudin-5 and occludin), contributing to BBB disruption, and also affect surrounding brain tissue (42–44). MMP-9 decreases myelin basic protein levels, contributing to white matter damage, while dysfunctional endothelial cells secrete elevated heat shock protein 90α (HSP90α), which impairs oligodendrocyte maturation (45, 46). Genetic factors, including MMP-2 single nucleotide polymorphisms, may influence enzyme expression and exacerbate endothelial dysfunction (45).

Elevated vWF levels in cSVD patients indicate heightened procoagulant states and endothelial injury, particularly associated with WMH and lacunar infarcts (47, 48). PAI-1, a potent fibrinolysis inhibitor, contributes to thrombotic risk by inhibiting tissue plasminogen activator, leading to clot persistence in cerebral vasculature (49, 50).

As a fibrin degradation product, elevated D-dimer levels reflect ongoing clot formation and dissolution (51). In cSVD, increased D-dimer is particularly associated with basal ganglia lacunar infarcts, suggesting microthrombotic processes, though its predictive value for cSVD progression requires further validation (52).

VEGF-A promotes endothelial cell proliferation and angiogenesis. Elevated circulating levels correlate with cerebral microbleeds in Alzheimer’s disease patients and predict increased stroke/TIA risk over 10-year periods (53, 54). Notably, VEGF-A shows specific association with microbleeds but not with WMH, suggesting distinct pathogenic pathways within cSVD (55).

HGF enhances VEGF-A-driven angiogenesis and shows broad associations with cSVD markers, including WMH, lacunes, microbleeds, and chronic microinfarcts. Elevated HGF levels in cognitive impairment and Alzheimer’s disease likely represent compensatory vascular repair attempts, though these may be insufficient to counterbalance ongoing injury (56).

Pharmacological strategies aimed at improving endothelial function have shown promise in managing cSVD. One of the primary pharmacological interventions is antiplatelet therapy, which is commonly used in ischemic stroke. The administration of antiplatelet agents such as aspirin has been shown to reduce recurrent stroke risk by about 30% after acute subcortical infarction (57). By reducing platelet aggregation, these drugs may help mitigate microvascular injury, which is a key contributor to endothelial damage in cSVD. However, antiplatelet therapy also carries significant risks, such as an increased risk of bleeding. In some patients, especially those with a history of gastrointestinal ulcers or other bleeding disorders, the use of antiplatelet agents may lead to severe hemorrhagic events, potentially outweighing the benefits (58). Moreover, there is evidence of interindividual variability in the response to antiplatelet drugs, with some patients failing to achieve the expected antiplatelet effect, limiting the universal effectiveness of this treatment approach.

Antihypertensive therapy is another cornerstone of cSVD management. Elevated blood pressure is a significant risk factor for endothelial dysfunction and the progression of WMH. Intensive antihypertensive treatment has been associated with less progression of WMH compared to standard guidelines for blood pressure reduction (59). By reducing systemic vascular resistance, antihypertensive agents alleviate the hemodynamic stress on small vessels, thereby reducing endothelial injury. Nevertheless, overly aggressive antihypertensive treatment can also pose risks. Excessive blood pressure reduction may lead to cerebral hypoperfusion, especially in patients with pre-existing cerebrovascular stenosis, potentially triggering ischemic events (60). Additionally, some antihypertensive medications may have adverse side effects, such as electrolyte imbalances or sexual dysfunction, which can affect patient compliance and the long-term effectiveness of the treatment (61).

Statin therapy, primarily used for lipid-lowering, has also been investigated for its potential benefits in cSVD. Statins, such as low-dose rosuvastatin, have been found to slow WMH progression, suggesting that their effects on endothelial function may extend beyond cholesterol reduction (62). Statins may exert direct beneficial effects on endothelial cells by enhancing endothelial nitric oxide production, which in turn improves vascular relaxation and reduces endothelial cell apoptosis. However, the Prevention of Decline in Cognition after Stroke Trial (PODCAST) showed limited effects of statins and blood pressure management on cognitive decline, indicating that the impact of statin therapy on cSVD-related cognitive outcomes may be more complex than initially thought (63). Moreover, statins are associated with a range of side effects, including muscle pain, liver enzyme elevation, and an increased risk of new-onset diabetes, which may limit their long-term use in some patients. Although these therapies remain a standard approach to preventing further cerebrovascular damage in cSVD patients (64), it is crucial to carefully weigh the benefits and risks for each individual patient.

Beyond conventional pharmacological therapies, there is growing interest in novel interventions that specifically target endothelial stabilization and repair. Cilostazol, a phosphodiesterase inhibitor, has shown potential in preclinical studies as a means to enhance endothelial function and reduce cerebrovascular damage in cSVD. By promoting endothelial cell survival and stabilizing the microvasculature, cilostazol has been found to reduce cognitive decline and ameliorate gliovascular damage in animal models of cSVD (65). However, translating preclinical findings to clinical practice presents significant challenges. The results from preclinical studies may not always be replicated in human trials due to differences in pathophysiological mechanisms between animals and humans. Additionally, ongoing clinical trials, such as the Lacunar Intervention (LACI-1 and LACI-2) studies, are investigating the efficacy of cilostazol in treating cSVD-related cognitive decline, but these trials are still in progress. There is a risk that the trials may not meet their primary endpoints, and even if they do, the therapeutic window of cilostazol may be narrow, requiring careful dosing and monitoring. Moreover, potential side effects of cilostazol, such as headache, nausea, and palpitations, may limit patient tolerance and compliance, which need to be thoroughly evaluated in larger-scale clinical trials. These trials may provide further insight into endothelial-targeted therapies for cSVD (66, 67), but it is essential to approach the development of cilostazol-based treatments with caution.

Endothelial dysfunction in cSVD is often accompanied by neuroinflammation, which exacerbates vascular injury. Minocycline, an anti-inflammatory agent, has demonstrated potential in alleviating endothelial injury and reducing white matter damage in cSVD models. In preclinical studies, minocycline has been shown to decrease neuroinflammation, improve white matter integrity, and enhance cognitive performance in animal models of cSVD (68). Its ability to modulate immune responses and protect endothelial cells makes it a promising candidate for further exploration in clinical settings. Other anti-inflammatory agents, including fingolimod, natalizumab, and rituximab, have shown efficacy in neuroinflammatory conditions and may be potential therapies for endothelial protection in cSVD (69). However, these agents also carry significant risks. Fingolimod is associated with bradycardia and an increased risk of infections, natalizumab has been linked to progressive multifocal leukoencephalopathy, a rare but serious viral brain infection, and rituximab can cause infusion-related reactions and immunosuppression. These risks highlight the need for careful patient selection, close monitoring, and further research to determine the safety and effectiveness of anti-inflammatory therapies for cSVD.

Stem cell therapy, particularly mesenchymal stem cells (MSCs), holds great promise for the treatment of cSVD by directly targeting endothelial injury and improving microvascular function. MSC transplantation has been shown to enhance BBB integrity, remodel the microvasculature, and reduce amyloid-beta (Aβ) accumulation in animal models of cSVD, leading to improved cognitive function (70). Additionally, MSCs have been found to increase the density of the pial microvascular network, suggesting that they may have the ability to restore cerebral blood flow (CBF) in cSVD by repairing damaged endothelial structures (71).

The use of oligodendrocyte progenitor cells (OPCs) and glial-restricted progenitors (GRPs), which have the potential to differentiate into oligodendrocytes and remyelinate damaged white matter, is another promising strategy. These cells could potentially repair the structural damage to white matter in cSVD, improving both functional and structural outcomes in the brain (72, 73). The use of stem cell populations that promote endothelial repair and white matter regeneration represents a novel approach to addressing both the vascular and neurological deficits in cSVD.