Non-neuronal cell-derived acetylcholine, a key modulator of the vascular endothelial function in health and disease

Abstract

Vascular endothelial cells play an important role in regulating peripheral circulation by modulating arterial tone in the microvasculature. Elevated intracellular Ca²⁺ levels are required in endothelial cells to induce smooth muscle relaxation via endothelium-dependent mechanisms such as nitric oxide production, prostacyclin, and endothelial cell hyperpolarization. It is well established that exogenous administration of acetylcholine can increase intracellular Ca²⁺ concentrations, followed by endothelium-dependent vasodilation. Although endogenous acetylcholine's regulation of vascular tone remains debatable, recent studies have reported that endogenously derived acetylcholine, but not neuronal cell-derived acetylcholine, is a key modulator of endothelial cell function. In this minireview, we summarize the current knowledge of the non-neuronal cholinergic system (NNCS) in vascular function, particularly vascular endothelial cell function, which contributes to blood pressure regulation. We also discuss the possible pathophysiological impact of endothelial NNCS, which may induce the development of vascular diseases due to endothelial dysfunction, and the potential of endothelial NNCS as a novel therapeutic target for endothelial dysfunction in the early stages of metabolic syndrome, diabetes, and hypertension.

Keywords: ACh; cardiovascular disease; endothelium-dependent vasodilation; exercise training; the non-neuronal cholinergic system.

Figure 1

A putative endothelial non-neuronal cholinergic system that regulates endothelium-derived relaxing factors (EDRFs) modulating vascular tone. Increased shear stress stimulates vascular endothelial cells to release ACh. The endothelial cell-derived ACh (eACh) affects the endothelial function in an autocrine manner. Local inflammation recruits activated ChAT-positive T cells, which release ACh. The T cell-derived ACh (tACh) is also suggested to affect endothelial function. In a healthy, normotensive condition, ChAT in endothelial cells contributes to the synthesis of eACh. It is hypothesized that adequate storage and release of eACh maintains basal vascular tone. Meanwhile, endothelial ChAT decreases in the condition of hypertension. Thus, it causes decreased eACh synthesis that results in increased vascular tone.