Endothelial dysfunction defined as the impaired ability of vascular endothelium to stimulate vasodilation plays a key role in the development of
atherosclerosis and in various pathological conditions which predispose to
atherosclerosis, such as
hypercholesterolemia,
hypertension,
type 2 diabetes, hyperhomocyst (e) inemia and
chronic renal failure. The major cause of the endothelial dysfunction is decreased bioavailability of
nitric oxide (NO), a potent
biological vasodilator produced in vascular endothelium from
L-arginine by the endothelial
NO synthase (eNOS). In
vascular diseases, the bioavailability of NO can be impaired by various mechanisms, including decreased NO production by eNOS, and/or enhanced NO breakdown due to increased oxidative stress. The deactivation of eNOS is often associated with elevated plasma levels of its endogenous inhibitor,
N(G) N(G)-dimethyl-L-arginine (ADMA). In
hypercholesterolemia, a systemic deficit of NO may also increase the levels of
low density lipoproteins (
LDL) by modulating its synthesis and metabolism by the liver, as suggested by recent in vivo and in vitro studies using organic NO donors. Therapeutic strategies aiming to reduce the risk of
vascular diseases by increasing bioavailability of NO continue to be developed.
Cholesterol-lowering drugs,
statins, have been shown to improve endothelial function in patients with
hypercholesterolemia and
atherosclerosis. Promising results were also obtained in some, but not all,
vascular diseases after treatment with
antioxidant vitamins (C and E) and after administration of eNOS substrate,
L-arginine, or its cofactor,
tetrahydrobiopterin (BH(4)). Novel strategies, which may produce beneficial changes in the vascular endothelium, include the use of natural extracts from plant foods rich in
phytochemicals.