Endothelial Dysfunction: Clinical Implications in Cardiovascular Disease and Therapeutic Approaches

Abstract

Atherosclerosis is a chronic progressive vascular disease. It starts early in life, has a long asymptomatic phase, and a progression accelerated by various cardiovascular risk factors. The endothelium is an active inner layer of the blood vessel. It generates many factors that regulate vascular tone, the adhesion of circulating blood cells, smooth muscle proliferation, and inflammation, which are the key mechanisms of atherosclerosis and can contribute to the development of cardiovascular events. There is growing evidence that functional impairment of the endothelium is one of the first recognizable signs of development of atherosclerosis and is present long before the occurrence of atherosclerotic cardiovascular disease. Therefore, understanding the endothelium's central role provides not only insights into pathophysiology, but also a possible clinical opportunity to detect early disease, stratify cardiovascular risk, and assess response to treatments. In the present review, we will discuss the clinical implications of endothelial function as well as the therapeutic issues for endothelial dysfunction in cardiovascular disease as primary and secondary endothelial therapy.

Keywords: Atherosclerosis; Cardiovascular Disease; Endothelium.

Fig. 1. An overview of the effects of vascular endothelial factors on the function of vascular smooth muscle and circulating blood cells. In the healthy endothelium, the eNOS is responsible for most of the vascular NO production. However, eNOS becomes a potential ROS generator when in the pathological uncoupled state, due to various oxidative stresses. ACE, angiotensin-converting enzyme; Ach, acetylcholine; AT-I, angiotensin I; AT-II, angiotensin II; AT₁, angiotensin 1 receptor; BH4, tetrahydrobiopterin; BK, bradykinin; cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; ECE, endothelin converting enzyme; eNOS, endothelial nitric oxide synthase; EDHF, endothelium derived hyperpolarizing factor; ET_A and ET_B, endothelin A and B receptors; ET-1, endothelin-1; L-Arg, L-arginine; L-Cit, L-citrulline; M, muscarinic receptor; O₂^-, superoxide anion; ONOO^-, peroxynitrite; NADPH, nicotinamide adenine dinucleotide phosphate; NO, nitric oxide; NOX, nicotinamide adenine dinucleotide phosphate oxidase; PGH₂, prostaglandin H₂; PGI₂, prostaglandin I₂; ROS, reactive oxygen species; S1_B, serotonin receptor; TP, thromboxane prostanoid receptor; TXA₂, thromboxane; 5-HT, serotonin; Θ, inhibition; ⊕, stimulation.

Fig. 2. Progression from risk factors to atherosclerosis and cardiovascular disease mediated by oxidative stress and endothelial dysfunction. The early detection of endothelial dysfunction is a critical point in the prevention of atherosclerosis and cardiovascular disease because this dysfunction could be an initial reversible step in the process of atherosclerosis.

Fig. 3. Therapeutic approaches to endothelial dysfunction. Endothelial therapy can be achieved with primary endothelial therapy for prevention of healthy endothelial function by controlling cardiovascular risk factors and secondary endothelial therapy for to improve dysfunctional endothelial homeostasis by treating underlying cardiovascular risk factors and cardiovascular disease. CV, cardiovascular; PAOD, peripheral arterial occlusive disease.