Potential of functional flavonoids in targeting vasospasm through modulation of oxidative stress and SPC-induced signaling pathways

Abstract

Vasospasm is a sustained abnormal contraction of vascular smooth muscle (VSM), which is commonly observed in the coronary and cerebral arteries. This abnormal VSM contraction leads to reduced blood flow to tissues or organs, ultimately causing severe diseases such as myocardial infarction and cerebral infarction. Studies have demonstrated that oxidative stress and sphingosylphosphorylcholine (SPC)-induced Rho-kinase signaling pathways are related to this abnormal contraction. Flavonoids, a class of natural compounds, are found in various plants, fruits, vegetables, and traditional Chinese medicines. They have anti-inflammatory, antioxidative, and anticarcinogenic properties. Recent studies have shown that some flavonoids strongly inhibit the abnormal contraction of VSM. This review explores the potential of flavonoids as candidate drugs for the treatment and prevention of vasospasm through oxidative stress and the SPC-induced Rho-kinase signaling pathway. Nevertheless, more extensive studies are required to fully elucidate the mechanism by which flavonoids exert their anti-vasospastic effects and explore their potential benefits as adjunctive therapy for critical cardiovascular and cerebrovascular diseases.

Keywords: ROS; SPC; flavonoids; oxidative stress; vasospasm.

FIGURE 1

Oxidative stress-induced signaling pathways involved in vasospasm. Oxidative stress damages endothelial cell function and increases the expression of endothelin-1 (ET-1) by increasing the generation of reactive oxygen species (ROS), while inhibiting the vasodilator factor NO, increasing vasoconstriction and weakening vasodilation. In addition, ROS activate key signaling pathways of vascular smooth muscle cells, including NF-κB, Rho-kinase, and MAPK, leading to inflammation and vascular dysfunction, playing a key role in development of vasospasm.

FIGURE 2

SPC-induced signaling pathways involved in vasospasm. SPC-mediated signaling pathway involves Fyn, a Src family kinase, which promotes Rho-kinase activation by interacting with paxillin. In addition, SPC can activate NADPH oxidase (NOX) through PLC and PKC, increasing ROS generation, which activates the Rho-kinase. The activated Rho-kinase phosphorylates myosin light chain phosphatase (MLCP) to inactivate it, and myosin light chain (MLC) remains in a highly phosphorylated state, leading to vasospasm.

FIGURE 3

The basic backbone structure of flavonoids and representative compounds of their category.

FIGURE 4

Schematic diagram of flavonoids preventing and treating vasospasm by regulating oxidative stress and SPC-induced signaling pathways.