Endothelial dysfunction: the early predictor of atherosclerosis

Abstract

Since the discovery in the 1980s that nitric oxide (NO) is in fact the elusive endothelium-derived relaxing factor, it has become evident that NO is not only a major cardiovascular signalling molecule, but that changes in its bioavailability are crucial in determining whether atherosclerosis will develop or not. Sustained high levels of harmful circulating stimuli associated with cardiovascular risk factors such as diabetes mellitus elicit responses in endothelial cells that appear sequentially, namely endothelial cell activation and endothelial dysfunction (ED). ED, characterised by reduced NO bioavailability, is now recognised by many as an early, reversible precursor of atherosclerosis. The pathogenesis of ED is multifactorial; however, oxidative stress appears to be the common underlying cellular mechanism in the ensuing loss of vaso-active, inflammatory, haemostatic and redox homeostasis in the body's vascular system. The role of ED as a pathophysiological link between early endothelial cell changes associated with cardiovascular risk factors and the development of ischaemic heart disease is of importance to basic scientists and clinicians alike.

Fig. 1.

Exposure of endothelial cells to cardiovascular risk factors and the resultant pathophysiological changes, i.e. endothelial activation and dysfunction, with progression to atherosclerosis if risk-factor exposure is sustained.

Fig. 2.

Synthesis of NO, downstream mechanisms and physiological effects. NO is synthesised by eNOS in the endothelial cells and diffuses into the underlying vascular smooth muscle cells (VSMCs), where it activates the second messenger, cyclic guanosine monophosphate (cGMP). Further downstream, signalling eventually leads to VSMC relaxation and vasodilation. In addition, NO regulates vascular homeostasis by anti-oxidation, anti-inflammatory and anti-platelet aggregation effects.

Fig. 3.

Coupled and uncoupled eNOS. (A) In the presence of sufficient levels of substrates and co-factors, and the absence of harmful reactive species, eNOS monomers will form a dimerised, coupled enzyme and produce physiological amounts of NO. (B) Decreased levels of the substrate, L-arginine and/or harmful effects exerted by increased levels of ONOO–, cause failure of the enzyme to dimerise, leading to the uncoupling of eNOS and the production of O₂– instead of NO.

Fig. 4.

Pathophysiological effects and the interplay between increased plasma cholesterol and O₂– levels, and endothelial cell responses.

Fig. 5.

Oxidative and nitro-oxidative stress. Superoxide anion (O₂–) released from sources such as NADPH oxidase, mitochondria and xanthine oxidase is dismutated to hydrogen peroxide (H₂O₂) by superoxide dismutase (SOD), which is then converted to water and oxygen by catalase. However, O₂– has a higher affinity for NO than SOD, and when in excess, it preferentially combines with NO to produce peroxynitrite with various pathophysiological consequences.