Therapeutic Potential of Remote Ischemic Conditioning in Vascular Cognitive Impairment

Rui Xu, Qianyan He, Yan Wang, Yi Yang, Zhen-Ni Guo, Rui Xu, Qianyan He, Yan Wang, Yi Yang, Zhen-Ni Guo

Abstract

Vascular cognitive impairment (VCI) is a heterogeneous disease caused by a variety of cerebrovascular diseases. Patients with VCI often present with slower cognitive processing speed and poor executive function, which affects their independence in daily life, thus increasing social burden. Remote ischemic conditioning (RIC) is a non-invasive and efficient intervention that triggers endogenous protective mechanisms to generate neuroprotection. Over the past decades, evidence from basic and clinical research has shown that RIC is promising for the treatment of VCI. To further our understanding of RIC and improve the management of VCI, we summarize the evidence on the therapeutic potential of RIC in relation to the risk factors and pathobiologies of VCI, including reducing the risk of recurrent stroke, decreasing high blood pressure, improving cerebral blood flow, restoring white matter integrity, protecting the neurovascular unit, attenuating oxidative stress, and inhibiting the inflammatory response.

Keywords: cerebral blood flow; inflammation; neurovascular unit; oxidative stress; remote ischemic conditioning; vascular cognitive impairment; white matter.

Conflict of interest statement

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.

Copyright © 2021 Xu, He, Wang, Yang and Guo.

Figures

FIGURE 1
FIGURE 1
Potential role of RIC on VCI-related risk factors. (A) Following an abrupt rupture of an atherosclerotic plaque, platelets respond rapidly through adhesion and aggregation, then thrombins generate a fibrin network to reinforce platelet aggregation and trap a large number of red blood cells, leading to the formation of thrombosis and vascular occlusion. The immune system are also involved in this process through activating the leukocytes and releasing large amount of cytokines. RIC is proven to reduce stroke recurrence in sICAS patients. The underlying mechanisms may involve the attenuation of excessive platelet aggregation and inflammation and the promotion of coagulation system. (B) Hypertension is characterized by and increased vascular resistance, which plays an important role in VCI. Vascular remodeling occurs at the early stage in hypertension and is associated with chronic inflammation response, hypertrophy of vascular smooth muscle cells (VSMCs) and deposition of extracellular matrix. RIC is efficient in blood pressure lowering in both hypertensive and prehypertensive patients. One of underlying mechanisms is the suppression of pathological vascular remodeling and downregulation of inflammation response.
FIGURE 2
FIGURE 2
Potential effects of RIC on VCI pathobiologies. The beneficial effects of RIC on VCI is associated with (A) increased CFB: the NOTCH1 signaling pathway may be involved in angiogenesis, which increases vascular diameter and promotes collateral formation. The eNOS/Nitrite/NO system plays an important role in the process of angiogenesis. The sheer stress induced by RIC upregulates the synthesis of eNOS in triggered organ and increases the concentration of nitrite in the circulation (not shown in this illustration). Nitrite reduces to NO under hypoxia condition and promotes new capillary formation. In addition, NO is an essential vasoactive agent in the regulation of vascular tension and cerebral autoregulation. (B) improved WM integrity (C) decreased neuronal death (D) restoration of endothelial function (E) reduced oligodendrocyte loss: the potential underlying mechanism is associated with decreased apoptosis of oligodendrocytes through activation of the PTEN/Akt/mTOR pathway. (F) attenuated oxidative stress: RIC can upregulate the expression of Nrf2 and attenuate the oxidative stress induced by hypoperfusion through promoting the expression of anti-oxidant enzymes, such as GSH and HO-1. This may partially mediated by the elevation of ET-1 in the plasma, which further upregulates the concentration of H2S within the brain. (G) decreased inflammation response: RIC can decrease the systemic inflammation by downregulating the level of inflammatory cytokines and leukocyte count. Meanwhile, RIC can mitigate neuroinflammation as evidenced by decreased expression of IBA-1 and GFAP, which are the markers of reactive microglial and reactive astrocytes, respectively. The expression of ICAM-1 and VCAM-1, markers of endothelial activation, are also downregulated. In addition, this was accompanied with less deposition of Ab protein.

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