Endothelial Dysfunction in Atherosclerosis

Abstract

Endothelial injury or dysfunction has been proposed to be one of the initiating events of atherosclerosis and is associated with an apparent decrease in the production of the vasodilator autacoid nitric oxide (NO). The nature of the endothelial dysfunction resulting in an attenuation of NO-mediated responses is unknown although possibilities include decreased substrate availability, decreased expression of the NO synthase, imbalance between the production of endothelium-derived constricting and relaxing factors, production of an endogenous NO synthase inhibitor and overproduction of oxygen-derived free radicals. While experimental evidence has been provided to support almost all of these possibilities, increased production of superoxide anions within the vascular wall is currently favoured as an explanation for the observed changes in vascular responsiveness and the characteristic loss of the anti-adhesive properties of the endothelium in the early stages of atherosclerosis. The altered ratio of NO/superoxide anion (O₂ production has been proposed to alleviate intrinsic inhibition of the transcription factor NFkB and lead to enhanced expression of adhesion molecules and chemotactic factors at the endothelial surface. The aim of this short review is to summarise recent findings which suggest that an imbalance in the production of NO and O₂ within the vascular wall is one of the earliest events to occur in the atherogenic process.

Vascular Relaxation by the Methanol Extract of Sorbus Cortex via NO-cGMP Pathway

“…A reduced production of NO by vascular endothelial cells is closely associated with the endothelial dysfunction or injury, which is proposed to be an important factor in severe pathologies such as atherosclerosis and hypertension. 27) Chronic inhibition of NO synthesis with the administration of inhibitor of NOS causes a vascular inflammation as well as hypertension in animal experiments. Therefore, the development of vasodilators acting by restoring the level of NO-cGMP in the vascular system can be of great value for the treatment of these cardiovascular diseases.…”

Interleukin-10 Induction of Nitric-oxide Synthase Expression Attenuates CD40-mediated Interleukin-12 Synthesis in Human Endothelial Cells

“…Whereas excessive NO formation due to induction of NOS-2 in combination with an increased generation of superoxide might be responsible for inflammation-induced tissue damage (12), potent anti-inflammatory properties have been ascribed to NOS-3-derived NO (11,27). However, in the early phase of an inflammatory episode the low endothelial cell NO output, which is further decreased through cytokine-mediated down-regulation of NOS-3 expression, may not be sufficient to effectively limit the pro-inflammatory response.…”

“…Whether endothelial cells promote or attenuate inflammatory responses to a large part seems to hinge on the level of nitric oxide (NO) production in these cells. NO is a highly potent anti-inflammatory agent that has been demonstrated to retard the progression of atherosclerosis (11) and to inhibit the development of other chronic inflammatory diseases (12).…”

17β-Estradiol reverses shear-stress-mediated low density lipoprotein modifications

“…Several reports suggest that the atheroprotective effect of E 2 may be mediated by increased local concentrations of ·NO [9,56] through up-regulation of eNOS expression [57] and/or an estrogen receptor-mediated activation of eNOS via the phosphatidylinositol-3-(PI3) kinase/ Akt kinase pathway [58,59]. E 2 transcriptionally up-regulates cytochrome P450 (CYP) activity leading to the enhanced arteriolar vasodilation response to shear stress in ·NO-deficient female rats and mice [1].…”