Cerebral small vessel disease (CSVD) is a syndrome with various structural or functional lesions involving perforating vessels that leads to parenchymal injury, which causes clinical, cognitive, neuroimaging, and neuropathological manifestation. Neuroimaging features are diverse so that the total CSVD score was created to capture the overall effect of CSVD on the brain, which incorporates white matter hyperintensity (WMH), cerebral microbleeds (CMB), lacunes, and enlarged perivascular spaces (EPVS; Huijts et al., 2013; Staals et al., 2014). The pathogenesis of the CSVD is not well known, but more evidence suggests that endothelial dysfunction is a crucial link leading to changes in cerebrovascular structure and function in patients with CSVD (Wardlaw et al., 2013; Jackman and Iadecola, 2015). Therefore, searching for endothelial biological markers will provide an essential theoretical basis for in-depth exploration of the pathogenesis of CSVD and the search for new therapeutic targets.

For CSVD, the related markers such as endothelial cell injury, inflammatory response, and coagulation/coagulation markers are well studied, and the connection between homocysteine, asymmetric dimethylarginine (ADMA), von Willebrand factor (VWF), and CSVD has been widely recognized (Wang et al., 2016; Janes et al., 2019; Nam et al., 2019). VWF is considered as a marker of endothelial dysfunction, which was synthesized in endothelial cells and released into the blood circulation via a constitutive pathway (released immediately after completion of molecular synthesis) or a stimulatory regulatory pathway that mediates initial platelet adhesion at sites of vascular injury (Ruggeri, 1999; Lenting et al., 2010). A disintegrin and metalloproteinase with a thrombospondin motif repeat 13 (ADAMTS13) regulate the activity of VWF by cutting ultra-long VWF multimers into smaller, less active molecules and exert its anti-inflammatory and antithrombotic properties (Gerritsen et al., 2001).

Several studies have reported that VWF levels are associated with the degree of WMH and the number of silent subcortical infarctions (Kario et al., 2001; Gottesman et al., 2009), but little is known about the association of VWF and ADAMTS13 activity with subtypes of CSVD and the overall CSVD burden. Therefore, we performed this study to investigate the independence or interactions correlation between multiple CSVD subtypes and the severity of CSVD.

In our study, we investigated the association between plasma VWF level, ADAMTS13 activity, and neuroimaging features of CSVD, including the overall CSVD burden. After adjustment for established CSVD-related risk factors, we confirmed that ADAMTS13 activity was reversely correlated to WMH, SI, and overall CSVD burden independently.

The prevalence of CSVD in the elderly population over 60 years can reach 60%. Studies have shown that about 45% of dementia and 20% of stroke is caused by CSVD (Sudlow and Warlow, 1997; Gorelick et al., 2011). Furthermore, CSVD may double the risk of recurrent stroke (Debette and Markus, 2010). In recent years, large population-based studies report that low ADAMTS13 activity was correlated with a risk of ischemic stroke (Sonneveld et al., 2015) and dementia (Wolters et al., 2018) independent of other known demographic and cerebrovascular risk factors, but studies on the relationship between ADAMTS13 activity and CSVD are little. The association between VWF and neuroimaging markers of CSVD has been demonstrated, including silent lacunar cerebral infarcts, periventricular hyperintensity, and deep white matter hyperintensity (Kario et al., 2001; Gottesman et al., 2009; Nagai et al., 2012). However, it has not reflected changes between VWF with the overall CSVD burden. In our study, we demonstrated that higher VWF level and lower ADAMTS13 activity correlated with WMH and SI, but not with CMB after adjusting for traditional risk factors and brain variables. The complex mechanism involved is unknown, but there are several possible explanations as follows.

First, low ADAMTS13 activity may be associated with endothelial cell dysfunction. Endothelial dysfunction may lead to increased permeability of the blood-brain barrier (BBB), which not only interrupts the oxygen and nutrient supply to the brain but also leads to extravasation of blood components that damage the surrounding white matter regions (Zlokovic, 2008; Gorelick et al., 2011; Xu et al., 2015). Cao et al. (2019) observed that ADAMTS13-deficient mice promote BBB disruption and reduce microvascular and capillary perfusion, and cerebral blood flow by changing endothelial junctions. However, there is a tight link between WMH and BBB impairment that plays a crucial role in early white matter degeneration (Kerkhofs et al., 2021). For SI, its underlying mechanism may have partially overlapping pathophysiology with WMH, but somewhat different (Wardlaw et al., 2015; Lin et al., 2017). VWF, an indicator of endothelial dysfunction, is the first step in mediated adhesion of platelets to damaged endothelial cells in thrombus formation. When endothelial cells are dysfunctional, VWF will be released in the form of large-molecular-weight multimers, which aggravate vascular damage (Lip and Blann, 1997). ADAMTS13 alleviates thrombogenesis and inflammation by adjusting VWF size and regulates microvascular thrombosis by altering the interaction of VWF with platelets (Pillai et al., 2016; Gogia et al., 2017). A study has reported that increased levels of functional VWF accelerate the formation of more microthrombi in multiple SI elderly patients (Kario et al., 2001). In this study, we obtained similar results in VWF and found that low ADAMTS13 activity was an independent risk factor for multiple SIs, and there was no association between ADAMTS13 activity and VWF levels, similar to previous studies (Andersson et al., 2012; Sonneveld et al., 2015; Denorme et al., 2017).The possible reason is that low local ADAMTS13 activity is not sufficient to cleave the supramaximal VWF multimers, eventually leading to the formation of microthrombiin microvascular injury. A second possible reason is that ADAMTS13 activity accelerates atherosclerosis. In animal models, lack of ADAMTS13 was found to promote the formation of plaques and vascular inflammation by generating signals for recruitment and extravasation of monocytes in the early stages of atherosclerosis, which are the pathological changes associated with CSVD (Gandhi et al., 2012; Jin et al., 2012). Ultimately, this may trigger or worsen the development of CSVD.

Furthermore, we confirmed that the severity of the overall CSVD burden was negatively correlated with ADAMTS13 activity. In another study, Nezu et al. (2015) observed that endothelial dysfunction was related to the severity of CSVD by using flow-mediated dilation (FMD) to measure endothelium-dependent vasodilation. However, ADAMTS13 was shown to be able to augment microvascular endothelial endothelium-dependent dilation (EDR) dependent on PI3K/Akt pathway in vivo (Zhou et al., 2019). Therefore, this implies ADAMTS13 may have played an essential role in the development of CSVD.

The innovation of this study is that we first reported the association between plasma VWF level, ADAMTS13 activity, and neuroimaging features of CSVD, including the overall CSVD burden in the community cohort. However, there are some limitations as follows. First, this study is a single-center cross-sectional study, with a relatively small number of study subjects and the included biological marker indicators are not comprehensive enough. Because we could not integrate multiple CSVD biomarkers into a panel, it will help us understand the pathogenesis of CSVD better. Second, the activity of ADAMTS13 was also demographically statistically different among different races and regions, and the subjects we included were all from Shanghai, China, so our results need to be validated in a more extensive prospective study.

In conclusion, reducing ADAMTS13 activity is related to white matter hyperintensity and subcortical infarction, but not with cerebral microhemorrhage. In addition, this implied that ADAMTS13 may have played an essential role in the development of CSVD. Exploring the differences of various biomarkers between various neuroimaging features of CSVD, and the association of these markers with clinical manifestations of CSVD will help to deeply elucidate the pathogenesis of CSVD and may provide a new theoretical basis and new targets for the early prevention and treatment of CSVD.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Shanghai Fifth People’s Hospital, Fudan University. The patients/participants provided their written informed consent to participate in this study.

WS: conceptualization, data collection, experiment, formal analysis, and writing original draft. SZ and YL: data collection. WL: validation, supervision, and experiment. XY and DW: review and editing, provide guidance. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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