The walls of larger blood vessels comprise three layers: an inner intima (tunica intima) consisting of a thin layer of endothelial cells; a thick media (tunica media) containing smooth muscle and elastin filaments that provide elastic properties; and an outer adventitia (tunica adventitia) consisting of fibroblasts and nerves embedded in collagenous tissue (Fig. 21a). The layers are separated by inner and outer elastic lamina. In large vessels, the adventitia contains a network of blood vessels called the vasa vasorum (vessel of vessels) supplying the smooth muscle. Veins have a thinner media than arteries, and contain less smooth muscle. All three layers contain fibrous collagen, which acts as a framework to which cells are anchored.
Vascular smooth muscle cells are elongated, 15–100 μm in length, and tend to be orientated in a spiral around the vessel; the lumen therefore narrows as they contract. Cells are connected by gap junc- tions, allowing electrical coupling and depolarization to spread from cell to cell. The structure and function of smooth muscle are described in Chapter 15.
Capillaries and the smallest venules are formed from a single layer of endothelial cells supported on the outside by a 50–100-nm thick basal lamina containing collagen. The luminal surface is covered by a glycoprotein network called the glycocalyx. There are three basic types of capillary, varying in permeability (Fig. 21b). Continu- ous capillaries have a low permeability, as junctions between the endothelial cells are very tight and prevent the diffusion of lipophobic molecules of >10 000 Da. They are found in skin, lungs, central nervous system and muscle. Fenestrated capillaries have less tight junctions and the endothelial cells are also punctured by 50–100-nm pores (fenestrae); they are therefore much more permeable. They are found where large amounts of fluid or material need to diffuse across the capillary wall, including endocrine glands, renal glomeruli and intestinal villa. Discontinuous capillaries are found in bone marrow, liver and spleen, and have gaps large enough for red blood cells to pass through. The microcirculation is discussed further in Chapter 23.
Regulation of function and excitation–contraction coupling
Vasoconstriction (Fig. 21c). Most vasoconstrictors bind to receptors and cause a guanosine triphosphate-binding protein (G-protein)- mediated elevation in intracellular [Ca2+], leading to contraction. Important vasoconstrictors include endothelin-1, angiotensin II (Chapter 35) and the sympathetic transmitter noradrenaline (norepine- phrine) (Chapter 7).
Ca2+ release. Binding to a receptor activates phospholipase C, which generates the second messengers inositol trisphosphate (IP3) and diacylglycerol (DAG) from membrane phospholipids. IP3 binds to receptors on the sarcoplasmic reticulum (SR) causing Ca2+ chan- nels to open and Ca2+ to flood into the cytoplasm. This response may only be transient as the store rapidly empties, but may initiate capacitative Ca2+ entry (see below).
Ca2+ entry. Vasoconstrictors also cause depolarization, which acti- vates Ca2+ entry via L-type voltage-gated Ca2+ channels as in cardiac muscle (Chapter 19). Unlike cardiac muscle, most types of vascular smooth muscle do not generate action potentials, but instead depolari- zation is graded, allowing graded entry of Ca2+. Receptor operated channels (ROC) may also be activated, some by DAG, through which both Ca2+ and Na+ can enter the cell; the latter contributes to depolarization. IP3-stimulated emptying of Ca2+ stores can also directly activate store operated channels (SOC) in the membrane, causing capacitative Ca2+ entry.
Importantly, many agonists also cause Ca2+ sensitization of the contractile apparatus, i.e. more force for the same rise in Ca2+. This is mediated by Rho kinase, although protein kinase C, which is activated by DAG, may also be involved. The relative importance of the above mechanisms depends on the vascular bed and vasoconstrictor. In small-resistance arteries, depolarization and voltage-gated Ca2+ entry are probably most important. Most systemic arteries exhibit a degree of basal (myogenic) tone in the absence of vasoconstrictors.
Ca2+ removal and vasodilatation (Fig. 21d). Ca2+ is pumped back into the SR (sequestrated) by the smooth endoplasmic reticulum Ca2+ ATPase (SERCA) which can rapidly reduce cytosolic Ca2+. Ca2+ is also removed from the cell by a plasma membrane Ca2+ ATPase (PMCA) and Na+–Ca2+ exchange (NCX; Chapter 19). Most endogenous vasodilators cause relaxation by increasing cyclic guanosine monophosphate (cGMP) (e.g. nitric oxide, NO) or cyclic adenosine monophosphate (cAMP) (e.g. prostacyclin, β-adrenergic receptor agonists). These second messengers act via protein kinase G (PKG) or protein kinase A (PKA), respectively. Both PKG and PKA lower intracellular Ca2+, partly by stimulating SERCA and PMCA, and partly by hyperpolarizing the membrane (i.e. so voltage-gated Ca2+ entry is inhibited). L-type Ca2+ channel blocker drugs, such as verapamil or dihydropyridines, are clinically effective vasodilators.
The endothelium (Fig. 21e)
The endothelium plays a crucial role in the regulation of vascular tone. In response to substances in the blood or changes in blood flow, it can synthesize several important vasodilators, including NO (endothelium-derived relaxing factor, EDRF) and prostacyclin (prostaglandin I2, PGI2), as well as potent vasoconstrictors, such as endothelin-1 and thromboxane A2 (TXA2).
NO is synthesized by the endothelial nitric oxide synthase (eNOS) from l-arginine. eNOS activity and NO production are increased by factors that elevate intracellular Ca2+, including local mediators such as bradykinin, histamine and serotonin, and some neurotransmitters (e.g. substance P). Increased flow (shear stress) also stimulates NO production, and additionally activates prostacyclin synthesis. The basal production of NO continuously modulates vascular resistance, as it has been found that inhibition of eNOS causes the blood pressure to rise. NO also inhibits platelet activation and thrombosis (inappropriate clotting) (Chapter 9).
Endothelin-1 is an extremely potent vasoconstrictor peptide which is released from the endothelium in the presence of many other vasoconstrictors, including angiotensin II, antidiuretic hormone (ADH; vasopressin) and noradrenaline, and may be increased in disease and hypoxia. As endothelin receptor blockade causes a fall in the peripheral resistance of healthy humans, it seems to contribute to the maintenance of blood pressure.
The eicosanoids prostacyclin and TXA2 are synthesized by the cyclooxygenase pathway from arachidonic acid, which is made from membrane phospholipids by phospholipase A2. In most vessels prostacyclin is most important.