The endothelium not only mediates relaxation but is a source of contracting factors. Endothelium-dependent contractions are elicited by physical and chemical stimuli (i.e.,
hypoxia, pressure, and stretch) and
autacoids, local and circulating
hormones. The mechanism of endothelium-dependent contractions to
hypoxia involves withdrawal of
nitric oxide. The endothelial
cyclooxygenase pathway can produce
thromboxane A2,
prostaglandin H2, and
superoxide anions. The
peptide endothelin is a potent contracting factor; its production is stimulated by vasopressor
hormones, platelet-derived
factors, coagulation products, and
cytokines, whereas
endothelium-derived nitric oxide,
prostacyclin, and a smooth muscle cell-derived inhibitory factor reduce
endothelin production. In
hypertension, the release of
cyclooxygenase-dependent endothelium-derived contracting factors to stretch,
acetylcholine, and platelet-derived products is augmented. Vascular
endothelin production in
hypertension remains controversial but appears mostly normal; it is augmented in the presence of
vascular disease or
renal insufficiency. The endothelium-dependent inhibition of
endothelin-induced contractions is reduced in
hypertension while the reactivity of vascular smooth muscle may be normal, increased, or reduced. The potentiating effects of low concentrations of
endothelin on contractions to
norepinephrine are augmented with aging and
hypertension. In
atherosclerosis, the production of the
cyclooxygenase-dependent endothelium-derived contracting factors and
endothelin is enhanced. Thus, endothelium-derived contracting factors can profoundly affect vascular tone and counteract relaxing factors produced within the endothelium. In
hypertension and
atherosclerosis, the role of contracting factors appears to become more dominant, leading to an imbalance of endothelium-dependent vascular regulation.