Vasoconstriction (contraction of smooth muscle) in the tunica media of small arteries and arterioles reduces the luminal diameter of these vessels and increases vascular resistance. Vasoconstriction increases systemic blood pressure. In the past, vasoconstriction was thought to be mainly induced by nerve impulses or circulating hormones. Today it is known that endothelium-derived factors play an important role in both physiologic and pathologic mechanisms of the circulatory system. Members of the endothelin
FIGURE 13.12 • Molecular mechanism of blood vessel vasodilatation. Relaxation of smooth muscle cells in the wall of the blood vessel causes an increase of its diameter and decreases in vascular resistance and systemic blood pressure. Nitric oxide (NO) produced by the endothelial nitric oxide synthase (eNOS) in endothelial cells is an important molecule regulating relaxation of vascular smooth muscles. Other molecules include ADP, vascular endothelial growth factor (VEGF ), bradykinin, prostacyclin (PGI2), and endothelium-derived hyperpolarizing factor (EDHF ). Shear stress produced between erythrocytes and endothelial cells as well as VEGF activate eNOS, increasing the production of NO. Once NO is produced, it diffuses to the underlying smooth muscles and activates guanylate cyclase production of cGMP, which in turn activates cGMP-dependent protein kinase G (PKG) metabolic pathways, causing smooth muscle relaxation. Metabolic stress of endothelial cells caused by increased levels of ADP or PGI2 stimulates cAMP-activated protein kinase A (PKA) metabolic pathways in smooth muscles, causing their relaxation. In addition, EDHF opens the potassium channels, causing hyperpolarization of smooth muscle cell membranes, further leading to their relaxation. (Based on Noble A, Johnson R, Thomas A, Bass P. The Cardiovascular System. London, New York: Churchill Livingstone, 2005.) family of 21 amino acid peptides produced by vascular endothelial cells are the most potent vasoconstrictors. The family consists of three members: endothelin-1 (ET-1), endothelin-2 (ET-2), and endothelin-3 (ET-3). Endothelins act mainly as paracrine and autocrine agents and bind to their own receptors on the epithelial cells and vascular smooth muscles (Fig 13.13). The ET-1 is the most potent naturally occurring vasoconstricting agent that interacts with its ETA receptor on vascular smooth muscles.
High levels of ET-1 gene expression are associated with many diseases that are caused in part by sustained en-dothelium-induced vasoconstriction. These include systemic hypertension (see Folder 13.2), pulmonary hypertension, atherosclerosis, congestive heart failure, idiopathic cardiomyopathy, and renal failure. It is interesting to mention that snake venom from the Israeli burrowing asp (Atractaspis engaddensis) contains sarafotoxin, a highly toxic protein that exhibits a very high degree of sequence homology with ET-1. After it enters the circulation, it binds to ETA receptors and causes life-threatening, intense coronary vasoconstriction. This is remarkable because endothelin is a natural compound of the human vascular system, whereas sarafotoxin is a toxin in the snake venom. The other endothelium-derived vasoconstrictors include thromboxane A2 and prostaglandin
H2. Thromboxane A2 is synthesized from prostaglandin H2. In addition, decreased rate of NO production or inactivation of NO by the superoxide anion (O2–) has a stimulating effect on smooth muscle contraction (see Fig. 13.13).
Traditionally, arteries are classified into three types on the basis of size and the characteristics of the tunica media.