The changes in vascular morphology included stenosis, occlusion, and intima-media thickening, which are all characteristics of AS (Alhusaini et al., 2018). Occlusion of blood vessels can chronically disrupt central hemodynamics, cerebral perfusion, and cerebrovascular function. The cerebrovascular functions’ injury includes endothelium-dependent diastolic function and cerebrovascular auto-regulation function injury, namely vascular system damage (Aparicio et al., 2017; Ogoh, 2017). The most direct result of impaired cerebrovascular function is cerebral blood flow (CBF) change. The association between carotid AS and encephalatrophy provides evidence that decreased CBF may lead to encephalatrophy (Moroni et al., 2016). Brain atrophy is a precursor to VD (Tariq and Barber, 2018). Likewise, chronic hypoperfusion causes blood flow damage and neuroinflammation by activating microglia cells, eventually resulting in white matter lesion (WML) and neurodegeneration. WML leads to cognitive impairment and ultimately to VD (Bǎdescu et al., 2016; Lim et al., 2019).

AS alters stable blood flow pattern, which triggers chronic hypoperfusion (Nie et al., 2018). When the brain is under chronic ischemia, the small cerebral arteries expand to the maximum extent due to the compensatory mechanism, resulting in impaired cerebral vascular function (Nagata et al., 2016). Even transient ischemia will lead to hypoxia and hypoglycemia, stimulating neuronal excitotoxicity. The core of this toxicity is astrocyte activation. Intracellular mitochondrial autophagy increases intracellular calcium ion and activates glutamate activation accompanied by ATP release. In severe cases, neurons die (Lénárt et al., 2016; Shabir et al., 2018). In the experiment by Nie et al., the loss of neurons in the hippocampus of bilateral implantation of the shear stress modifier mice were observed with a decrease in glucose intake. The evidence demonstrates that a hypoxic environment also causes low sugar level (Nie et al., 2018). Low glucose level rapidly leads to endothelial dysfunction or induces endothelial cell mitochondrial autophagy, which results in nitric oxide (NO) bioavailability decrease, mitochondrial reactive oxygen species (ROS) production increase, and vascular function damage (Tanner et al., 2017). Of important note is that only elastic arterial lesions are associated with VD. VD patients have some degree of endothelial dysfunction, which may be explained by the arterial pulse system (Geijselaers et al., 2016). The increase of mitochondrial ROS and brain–blood barrier (BBB) permeability form a vicious cycle. They jointly cause the death of oligodendrocytes and the activation of microglia and astrocytes (Lim et al., 2019). Following the trajectory mentioned above, the series of processes induce WML and eventually form VD.

The NVU links the nervous and circulatory systems both functionally and structurally in the brain in response to the isolation of BBB. NVU damage leads to chronic hypoperfusion, hypoxia, excessive proinflammatory factor production, ROS production, and reduced NO utilization (Ramalho et al., 2018; Shabir et al., 2018). NO is a substance that stimulates vasodilation. The decrease in NO utilization indicates that vascular function is impaired. Importantly, CBF regulation in the aged more depends on this pathway (Karlsson et al., 2017). This may be the reason why they are more susceptible to VD. Meanwhile, the response of cerebral circulation to carbon dioxide (CO₂) is also damaged. CO₂ controls the increase and decrease of CBF by controlling the contraction and relaxation of cerebral blood vessels under normal conditions (Nagata et al., 2016). These damages further disrupt blood flow. The subsequent development of impaired blood flow is as previously described.

AS can directly trigger ROS production through the foam cells in atherosclerotic plaques, and then impair the cerebral vascular function through low bioavailability of NO or lead to WML by triggering neuroinflammation (Karlsson et al., 2017). It means that ROS can be secreted not only by other pathways but also directly by AS, which greatly increases the perniciousness of ROS. Paraoxonase-1(Pon-1) is an enzyme that exists in high density lipoprotein (HDL). When the activity of arylesterase (ARE), which catalyzes the hydrolysis of non-phosphorous ester in the Pon-1 mechanism, is reduced, the enzyme’s anti-atherosclerosis effect is impaired through antioxidant damage, thus promoting the AS process. The serum ARE activity in VD was also significantly decreased (Castellazzi et al., 2016). This provides theoretical support for AS directly causing VD through oxidative stress.

miRNAs are non-coding RNAs and play an important role in the progression of AS (Feinberg and Moore, 2016). Furthermore, miRNAs are involved in the expression of genes related to neuronal excitotoxicity, neuroinflammation, and BBB permeability increase (Tiedt and Dichgans, 2018). In AS, abnormal regulation of miRNAs contributes to the development of VD like the butterfly effect. miRNA-124 is a representative example. During the process of AS, miRNA-124 is down-regulated (Zhang et al., 2017). However, due to the variation, the gene regulatory procedures involved in it will develop toward a harmful direction such as excitatory toxicity, inflammation, and BBB destruction, eventually following the respective pathway to VD (Tiedt and Dichgans, 2018).

Different anatomical lesion locations of AS influence the mechanisms of AS causing VD. Here, we take the example of intracranial atherosclerosis (ICAS) and extracranial atherosclerosis (ECAS). The lesions of ICAS occur in the arteries surrounded by the skull and dura mater or located in the subarachnoid space (Qureshi and Caplan, 2014). This means that ICAS can shorten the above five pathways by taking advantage of its location and causes blood flow damage faster than ECAS. Interestingly, ICAS can lead to VD without other mechanisms (Simonetto et al., 2019). This is supported by a higher load of WMH surrounded by vulnerable atherosclerotic plaques in the cerebral hemisphere (Altamura et al., 2016). However, ECAS tends to cause VD through vascular morphogenesis and hemodynamic changes (Kim and Caplan, 2016). Since the descending aorta blood flow is separated from the cerebral circulation, we chose representative descending aorta AS to illustrate the point. In the study by Aparicio et al., descending aortic AS can generate significant encephalatrophy through vascular stenosis and vascular pulsating pressure increase (Aparicio et al., 2017). This is consistent with the vascular morphogenesis and hemodynamic change pathways mentioned above. It demonstrates that although ICAS and ECAS share five common pathogenetic mechanisms, they still have differences.

In addition to the fact that AS is directly associated with VD through its mechanisms, the two can be linked by stroke as a mediator. Because many reports only investigate the relationship between AS and stroke, and stroke can directly lead to VD, this paper describes this situation separately (Shabir et al., 2018). Stroke is divided into ischemic stroke and hemorrhagic stroke. AS plays a pathogenic role in stroke, and carotid AS leads to ischemic stroke through the athero-embolic mechanism. The incidence about the recurrence rate of stroke is gradually increasing associated with the increase of AS risk factors and the number of affected vessels (Heldner et al., 2018). VD may be caused by one or more stroke risk factors (Tariq and Barber, 2018). This provides theoretical support for VD mediated by stroke from AS. Herein, the relationship between AS and stroke will be analyzed from the perspectives of genes and molecules.

AS and stroke have a genetic correlation (Franceschini et al., 2018). For example, SH2B3 gene mutation leads to the deficiency of the LNK protein translated by it, which will aggrandize platelet production and activity, thereby accelerating AS. Furthermore, the gene is a risk site for stroke in GWAS (Dichgans et al., 2019). While the causal connection between the gene variations and the development of the two diseases is not elaborate, inflammatory cytokines released by AS can alter gene expression in peripheral blood cells, which suggests that AS may cause the gene mutations and increase the risk of stroke (Ferronato et al., 2019). The hope is that more research will focus on the sequence of genetic mutations and the two diseases in the future.

MCP-1 is a pro-inflammatory factor that plays a significant role in AS and stroke. Its obligation in AS is to recruit monocytes into the nidus. Therefore, the increased level of this factor will aggravate the condition of AS. Research shows MCP-1 level increase for genetic factors compounds the risk of stroke. It should be emphasized that MCP-1 levels are associated with the risk of ischemic stroke, not hemorrhagic stroke. This is consistent with the atherogenic characteristics of stroke (Georgakis et al., 2019). This means there is a close affinity between AS and stroke, people with a genetic variant that causes over normal MCP-1 level in AS have higher stroke risk.

There is vascular comparability between kidney and brain, so the pathogenesis of kidney disease and VD is similar (Saji et al., 2016). VD is the main cause of cognitive impairment in patients with chronic kidney disease (CKD) (Pépin and Villain, 2020). CKD produces uremic toxins, leads to BBB destruction, and causes neuron damage when the toxin enters the brain. While AS also increases the permeability of BBB, accelerating the ingress of uremic toxins and other hazardous substances into the brain and engendering brain damage (Chelluboina and Vemuganti, 2019). This means AS can not only play a dominant role in the pathogenesis of VD, but also act as an auxiliary factor in the development of VD caused by CKD. In this instance, AS is not a necessary condition to cause disease, but accelerates disease progression.

The gut microbiota (GM) communicates with the brain via hormones, nerves, and the immune system. It is an important component of the gut-brain axis, and studies have shown that GM can ameliorate the disease development of VD, which provides theoretical foundations for the correlation between GM and VD (Liu et al., 2015). There is GM DNA in Atherosclerotic plaques, suggesting that GM may place a premium on AS and/or participate in the progression of AS through inflammatory responses, lipids, and metabolites. AS and VD can be severally induced by GM. In addition, Helicobacter pylori (Hp) positive patients in VD have graver AS, which supports GM, AS, and VD to form a triangle. Furthermore, the GM expresses more opportunistic bacteria in stroke patients (Xu et al., 2016; Li et al., 2018). Consequently, it is inconclusive whether the severity of AS affects the susceptibility of GM or GM enhances the aggressiveness of AS. Further prospective research is needed to better ascertain the role of GM amongst AS in VD.

Apolipoprotein E (ApoE) ɜ4 is an allele and produces ApoE. It is a plasma protein involved in lipid metabolism and cholesterol transport (Yin et al., 2012). Carriers of ApoE ɜ4 are strongly associated with VD, and can increase the risk of VD. However, the data on the relationship between ApoE ɜ4 and VD should be used circumspectly for some data suggesting that ApoE ɜ4 and VD are irrelevant (Davidson et al., 2006). The allele is also correlated with higher serum cholesterol levels and the severity of AS in the early stages of youth (Hixson, 1991). β- and γ-secretases lyse the amyloid precursor protein and generate Amyloid beta 1-40 (Abeta40) peptides. The staple amyloid protein in human AS is Abeta40 (Stamatelopoulos et al., 2015). When Abeta40 is further cleaved, the products released are connected with the dominating pathological mechanism of VD (Chen et al., 2019). This may be the progression of ApoE ɜ4 participating in AS and VD. In this case, since AS and VD are both victims, the difference in the onset time of these two diseases may be due to the different course of disease.