Endothelium-Derived Relaxing Factors

The first vasoactive endothelial substance to be discovered was prostacyclin (PGI₂), a product of the cyclooxygenase pathway of arachidonic acid metabolism (Box 4-1). The production of PGI₂ is activated by shear stress, pulsatility of flow, hypoxia, and a variety of vasoactive mediators. Upon production it leaves the endothelial cell and acts in the local environment to cause relaxation of the underlying smooth muscle or to inhibit platelet aggregation. Both actions are mediated by the stimulation of adenylyl cyclase in the target cell to produce cyclic adenosine monophosphate (cAMP).

It has been shown that many physiologic stimuli cause vasodilation by stimulating the release of a labile, diffusible, nonprostanoid molecule termed endothelium-derived relaxing factor (EDRF), now known to be nitric oxide (NO). NO is the basis of a widespread paracrine signal transduction mechanism whereby one cell type can modulate the behavior of adjacent cells of a different type.^1,2 NO is a very small lipophilic molecule that can readily diffuse across biologic membranes and into the cytosol of nearby cells. The half-life of the molecule is less than 5 seconds so that only the local environment can be affected. NO is synthesized from the amino acid L-arginine by NO synthase (NOS). When NO diffuses into the cytosol of the target cell, it binds with the heme group of soluble guanylate cyclase, resulting in a 50- to 200-fold increase in production of cyclic guanosine monophosphate (cGMP), its second messenger. If the target cells are vascular smooth muscle cells, vasodilation occurs; if the target cells are platelets, adhesion and aggregation are inhibited.

It is likely that NO is the final common effector molecule of nitrovasodilators (including sodium nitroprusside and organic nitrates such as nitroglycerin). The cardiovascular system is in a constant state of active vasodilation that is dependent on the generation of NO. The molecule is more important in controlling vascular tone in veins and arteries compared with arterioles. Abnormalities in the ability of the endothelium to produce NO likely play a role in diseases such as diabetes, atherosclerosis, and hypertension. The venous circulation of humans seems to have a lower basal release of NO and an increased sensitivity to nitrovasodilators compared with the arterial side of the circulation.³

Endothelium-Derived Contracting Factors

Contracting factors produced by the endothelium include prostaglandin H₂, thromboxane A₂ (via cyclooxygenase), and the peptide endothelin. Endothelin is a potent vasoconstrictor peptide (100-fold more potent than norepinephrine).⁴

Endothelial Inhibition of Platelets

A primary function of endothelium is to maintain the fluidity of blood. This is achieved by the synthesis and release of anticoagulant (e.g., thrombomodulin, protein C), fibrinolytic (e.g., tissue-type plasminogen activator), and platelet inhibitory (e.g., PGI₂, NO) substances (Box 4-2). Mediators released from aggregating platelets stimulate the release of NO and PGI₂ from intact endothelium, which act together to increase blood flow and decrease platelet adhesion and aggregation, thereby flushing away microthrombi and maintaining the patency of the vessel.