The entire vascular lumen is lined by a monolayer of endothelial cells which are crucial in regulating vascular tone. Endothelial cells can release both constricting and dilating substances when stimulated by blood-borne substances or by shear stress associated with the flow of blood (Figure 24). Important endothelial vasodilators include nitric oxide (termed endothelium-derived relaxing factor prior to its identification in 1987), prostacyclin (PGI₂), and endothelium-derived hyperpolarizing factor (EDHF). The major endothelial vasoconstrictors are endothelin-1, thromboxane A₂ (TXA₂) and prostaglandin H₂.

Endothelial cells also have a crucial role in suppressing platelet aggregation and thereby regulating haemostasis (see Chapter 7) and, as the major constituents of the capillary wall, control vascular permeability to many substances (see Chapter 21).

Nitric Oxide

Nitric oxide (chemical formula NO) is the major vasodilator released by endothelial cells. NO is synthesized from the amino acid L-arginine and O₂ by nitric oxide synthase (NOS). The most important form of NOS in the cardiovascular system is endothelial NOS (eNOS, also NOS-3), which is thought to be responsible for a continual basal production and release of NO by endothelial cells (also by platelets and the heart). eNOS is further activated by a variety of substances that act on their receptors to increase the endothelial cell intracellular Ca²⁺ [Ca²⁺]_i, leading to raised levels of the Ca²⁺ – calmodulin complex which stimulates the enzyme. The rise in [Ca²⁺]_i is initiated by Ca²⁺ release from the endoplasmic reticulum, and is subsequently sustained at a lower but still elevated level by Ca²⁺ influx via store-operated Ca²⁺ channels (see Chapter 15). Substances that cause vasodilatation in this way include locally released factors such as bradykinin, adenine, adenosine nucleotides, histamine, serotonin and the neurotransmitter substance P. Acetylcholine has a similar effect, although this probably has little physiological importance in humans.

Shear forces exerted on the endothelium by the flow of blood also activate eNOS, and this contributes to both basal NO release and local regulation of bloodflow. This effect is not caused by a rise in [Ca²⁺]_i, but by cellular pathways activated by shear force-induced deformation of the endothelial cell cytoskeleton. One such pathway involves the sequential activation of the enzymes phosphatidylinositol 3-kinase (PI3K) and Akt, the latter of which stimulates eNOS via phosphorylation.

Once released from the endothelium, NO diffuses through the vascular wall and into the smooth muscle cells, where it activates the cytosolic enzyme guanylyl cyclase. This increases levels of cellular cyclic GMP, which causes relaxation as described in Chapter 15.

NO is a free radical (i.e. it contains an unpaired electron) and is therefore very reactive. In particular, upon its release NO reacts very rapidly with superoxide, another free radical which is continually being produced by a variety of enzymes (including eNOS) to form peroxynitrite

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