Smooth muscle and the cardiovascular and lymphatic systems

Microstructure of smooth muscle

Smooth muscle cells (fibres) are smaller than those of striated muscle. Their length can range from 15 μm in small blood vessels to 200 μm, and even to 500 μm or more in the uterus during pregnancy. The cells are spindle-shaped, tapering towards the ends from a central diameter of 3–8 μm ( Fig. 6.1 ). The nucleus is single, located at the midpoint, and often twisted into a corkscrew shape by the contraction of the cell. Smooth muscle cells align with their long axes parallel and staggered longitudinally, so that the wide central portion of one cell lies next to the tapered end of another. Such an arrangement achieves both close packing and a more efficient transfer of force from cell to cell. In transverse section, smooth muscle is seen as an array of circular or slightly polygonal profiles of very varied size, and nuclei are present only in the centres of the largest profiles ( Fig. 6.2 ). This appearance contrasts markedly with that of skeletal muscle cells, which show a consistent diameter in cross-section and peripherally placed nuclei throughout their length.

Smooth muscle has no attachment structures equivalent to the fasciae, tendons and aponeuroses associated with skeletal muscle. There is a special arrangement for transmitting force from cell to cell and, where necessary, to other soft tissue structures. Cells are separated by a gap of 40–80 nm. Each cell is covered almost entirely by a prominent basal lamina, which merges with a reticular layer consisting of a network of fine elastin, reticular fibres (collagen type III) and type I collagen fibres ( Fig. 6.3 ). These elements bridge the gaps between adjacent cells and provide mechanical continuity throughout the fascicle. The cell attaches to components of this extracellular matrix at dense plaques ( Fig. 6.3A , Fig. 6.4 ), where the basal lamina is thickened; cell–cell attachment occurs at intermediate junctions or small desmosome-like junctions, formed of two adjacent dense plaques. At the boundaries of fascicles, the connective tissue fibres become interwoven with those of interfascicular septa, so that the contraction of different fascicles is communicated throughout the tissue and to neighbouring structures. The components of the reticular network, the ground substance and collagen and elastic fibres, are synthesized by the smooth muscle cells themselves, not by fibroblasts or other connective tissue cells, which are rarely found within fasciculi.

The membrane of smooth muscle cells contains molecules such as proteoglycans, glycoproteins and glycolipids on its exterior surface that form a thin, negatively charged network, the glycocalyx. Whilst less studied than that of endothelial cells, the smooth muscle cell glycocalyx has been shown to be important for mechanotransduction in small blood vessels. There are also a number of cell membrane-spanning proteins that extend through the glycocalyx and interact with the extracellular matrix, including cadherins and integrins. These provide structural and signalling links with the extracellular matrix and other cells, e.g. at desmosomes. The cytosolic ends of these proteins interact with components of the cytoskeleton via a complex of other proteins and kinases, and provide an important signalling pathway linking cell function to the exterior, which can modulate, for example, gene transcription and phenotype ( ).

Discontinuities occur in the basal lamina between adjacent cells, and here the cell membranes approach to 2–4 nm of one another to form a gap junction (see Fig. 6.2 ). These junctions are structurally similar to their counterparts in cardiac muscle, and are formed by binding of adjacent connexon complexes on the surface of the two cells. They provide a low-resistance channel through which electrical excitation and small molecules can pass, e.g. enabling a coordinated wave of contraction. The incidence of gap junctions varies with the anatomical site of the tissue: they appear more abundant in the type of smooth muscle that generates rhythmic (phasic) activity. In addition, they link the endothelium functionally with the underlying smooth muscle (via myoendothelial gap junctions) in small resistance arteries and arterioles.

Caveolae, cup-like invaginations of the plasma membrane with a resemblance to endocytotic vesicles, are a characteristic feature of smooth muscle cells, and may form up to 30% of the membrane (see Fig. 6.4 ). They are associated with many receptors, ion channels, kinases and the peripheral sarcoplasmic reticulum, and may thus act as highly localized signalling microdomains. They may also act as specialized pinocytotic structures involved in fluid and electrolyte transport into the cell. Other organelles (mitochondria, ribosomes, etc.) are largely confined to the filament-free perinuclear cytoplasm, although in some smooth muscle types, including vascular smooth muscle, peripheral mitochondria, sarcoplasmic reticulum and sarcolemma form important signalling microdomains.

In some blood vessels, notably those of the pulmonary circulation, and in the airways and probably in other smooth muscle types, there is evidence for heterogeneity of cell phenotype. The smooth muscle cells of small blood vessels and bronchioles exhibit different functional properties from those in larger vessels and airways, and may differ in morphology, expression of signalling proteins such as ion channels, and excitation–contraction coupling mechanisms. Even within individual tissues there is evidence of heterogeneity. Some myofibroblast-like cells have a function that is more secretory than contractile. The secretory phenotype is often increased in disease (e.g. chronic severe asthma, pulmonary hypertension) and is associated with increased proliferation and remodelling, and with secretion of cytokines and other mediators. Many smooth muscles seem to exhibit considerable phenotypic plasticity between these contractile and secretory phenotypes ( ).

Neurovascular supply of smooth muscle

Innervation

Smooth muscle may contract in response to nervous or hormonal stimulation, mechanical deformation, or electrical depolarization transferred from neighbouring cells. Some muscles receive a dense innervation to all cells and are often referred to as multi-unit smooth muscles: most blood vessels are of this type. Such innervation can precisely define contractile activity, e.g. in the iris, specific nervous control can produce either pupillary constriction or dilation. Other muscles are more sparsely innervated and have been referred to as unitary smooth muscles. They tend to display myogenic activity, initiated spontaneously or in response to stretch, which may be markedly influenced by hormones. In these muscles, which include those in the walls of the gastrointestinal tract, urinary bladder, ureter, uterus and uterine tube, innervation tends to exert a more global influence on the rate and force of intrinsically generated contractions. The terms multi-unit and unitary smooth muscles are widely used, but in practice such distinctions are better regarded as the extremes of a continuous spectrum.

Smooth muscles are innervated by unmyelinated axons with cell bodies located in autonomic ganglia, either in the sympathetic chain or, in the case of parasympathetic fibres, closer to the point of innervation ( Fig. 6.5 ). They ramify extensively, spreading over a large area of the muscle and sending branches into the muscle fasciculi. The terminal portion of each axonal branch is beaded and consists of expanded portions, varicosities, packed with vesicles and mitochondria, separated by thin, intervaricose portions. Each varicosity is regarded as a transmitter release site and may be considered as a nerve ending in the functional sense. In this way the axonal arborization of a single autonomic neurone bears a very large number of nerve endings (up to tens of thousands), as opposed to a maximum of a few hundred in somatic motor neurones. The neuromuscular terminals of autonomic efferents are considered in more detail on p. 67 .

The neuromuscular junctions in smooth muscles do not show the consistent appearance seen in skeletal muscles. The neurotransmitter diffuses across a gap that can vary from 10 to 100 nm; even separations of up to 1 μm may still allow neuromuscular transmission to take place, although more slowly. The nerve ending is packed with vesicles but the adjacent area of the muscle cell is not structurally differentiated from that of non-junctional regions, i.e. there is no distinct synapse.

Intramuscular afferent nerves are the peripheral processes of small sensory neurones in the dorsal root ganglia. Since they are unmyelinated, contain axonal vesicles and have a beaded appearance, they are difficult to distinguish from efferent fibres, except by differential staining for neurotransmitters.

Structural basis of contraction

High-resolution immunocytochemistry of the internal architecture of the smooth muscle cell suggests a structural model for contractile function, which is illustrated in Fig. 6.3 . This depends on the interaction of two systems of filaments, one forming the cytoskeleton and the other the contractile apparatus.

Excluding the perinuclear region, the cytoplasm of a smooth muscle cell effectively consists of two structural domains. The cytoskeleton forms a structural framework that maintains the spindle-like form of the cell and provides an internal scaffold with which other elements can interact. Its major structural component is the intermediate filament desmin, with the addition of vimentin (which may also be present alone) in vascular smooth muscle. The intermediate filaments are arranged mainly in longitudinal bundles, but some filaments interconnect the bundles with each other and with the sarcolemma to form a three-dimensional network. The bundles of intermediate filaments insert into focal, electron-dense bodies, approximately 0.1 μm in diameter, which are distributed uniformly throughout the cytoplasm and also attach to dense plaques underlying the plasma membrane (see Fig. 6.3A ). The cytoplasmic dense bodies and submembraneous dense plaques are equivalent to the Z-discs of striated muscle cells. They contain the actin-binding protein α-actinin and thus also anchor the actin filaments of the contractile apparatus. These form a lattice of obliquely arranged bundles throughout the cytoplasm, which transmit force to the plasma membrane and thus the basal lamina and extracellular matrix via dense plaques. These are associated with a highly structured arrangement of ancillary proteins, including vinculin and talin, which in turn attach to integrins that cross the membrane and provide attachment to components of the extracellular matrix ( ).

An analogous arrangement underlies cell–cell attachment at desmosomes, but here the attachment between dense plaques is provided by transmembrane cadherin glycoproteins and intracellular catenins instead of integrins and talin. Mechanical deformation of the cell may be linked to cell signalling mechanisms via focal adhesion kinase (FAK) and its substrate paxillin; phosphorylation of talin and paxillin may modulate the deformability of the smooth muscle cell. Other regulatory proteins also associate specifically with actin, such as caldesmon and calponin. The cytoskeleton is not a passive structure. It adapts dynamically to load and is modulated by cell surface receptors including integrins and agonist binding to G-protein coupled receptors, and so contributes to contraction ( ). This presumably contributes to the low energy requirements of smooth muscle contraction because dynamic reorganization of the cytoskeleton following active contraction allows cell shortening to be maintained without further energy expenditure.

The ratio of actin to myosin is about eight times greater in smooth compared to striated muscle, reflecting the greater length of actin filaments in smooth muscle. Smooth muscle myosin filaments are 1.5–2 μm long, somewhat longer than those of striated muscle, and are formed of a slower isoform of myosin. Although smooth muscle cells contain less myosin, the longer filaments are capable of generating considerable force. The myosin filaments of smooth muscle are also assembled differently, such that their head regions lie symmetrically on either side of a ribbon-like filament, rather than imposing a bipolar organization on the filament. Actin filaments, to which they bind, can thus slide along the whole length of the myosin filament during contraction. In addition, dynamic polymerization of both myosin and actin monomers during activation can alter the length of the contractile filaments. These differences underpin the ability of smooth muscle to undergo much greater changes in length than striated muscle. Actin–myosin filament sliding generates tension, which transmits to focal regions of the plasma membrane, changing the cell to a shorter, more rounded shape ( Fig. 6.3B ) and often deforming the nucleus to a corkscrew-like profile.

Although some smooth muscles can generate as much force per unit cross-sectional area as skeletal muscle, the force develops much more slowly. Smooth muscle can contract by more than 80%, much greater than the 30% or so to which striated muscle is limited. The significance of this is illustrated by the urinary bladder, which is capable of emptying completely from an internal volume of 300 ml or more. Smooth muscles can maintain tension for long periods with very little expenditure of energy. Many smooth muscle structures are able to generate spontaneous contractions, examples are found in the walls of the intestines, ureter and uterine tube.

Excitation–contraction coupling in smooth muscle

Excitation–contraction coupling in smooth muscle is more complex than in skeletal or cardiac muscle, and may be electromechanical or pharmacomechanical. Electromechanical coupling involves depolarization of the cell membrane by an action potential, and may be generated when a membrane receptor, usually linked with an ion channel, is occupied by a neurotransmitter, hormone or other blood-borne substance. It is most commonly seen in unitary and phasic smooth muscles such as those of the viscera, with transmission of electrical excitation from cell to cell via gap junctions. In some types of smooth muscle depolarization may be the consequence of other stimuli, such as cooling, stretch and even light.

Pharmacomechanical coupling is a receptor-mediated and G-protein coupled process, and is the major mechanism in tonic smooth muscles such as in the vasculature and airways. It may involve several pathways, including formation of inositol trisphosphate, which triggers intracellular calcium release from the sarcoplasmic reticulum, activation of voltage-independent calcium channels in the sarcolemma, and depolarization causing activation of voltage-dependent calcium channels (reviewed in ). Many receptors also couple to kinases that modulate contraction in a calcium-independent fashion, either via myosin phosphatase (see below) or via the actin cytoskeleton (see above). The extent to which any of these pathways contributes to activation varies between different types of smooth muscle.

Whilst the regulation of contraction of smooth muscle is largely calcium-dependent, the effects of an elevation of intracellular calcium are mediated via myosin, not actin/tropomyosin as in cardiac and skeletal muscle. Most smooth muscles contain little or no troponin, and instead calcium binds to calmodulin. The calcium–calmodulin complex regulates the activity of myosin light chain kinase, which phosphorylates myosin regulatory light chains and initiates the myosin–actin adenosine 5′-triphosphatase (ATPase) cycle. The enzymatic activation process is therefore inherently slow. Myosin phosphatase dephosphorylates myosin and thus promotes relaxation. The degree of myosin phosphorylation and therefore contraction depends on the relative activities of myosin light chain kinase and myosin phosphatase. Thus inhibition of the phosphatase, e.g. by Rho kinase, increases phosphorylation for any level of calcium (i.e. increases calcium sensitivity). The latter is a central component of the response to many constrictor agonists.

Origin of smooth muscle

Smooth muscle cells develop from a range of mesenchymal sources: the muscularis layer of visceral tubular systems, e.g. gut, airways etc. derive from local splanchnopleuric mesenchyme, whereas the smooth muscle of the sphincter and dilator pupillae is derived from neurectoderm. The origin of the tunica media of blood and larger lymphatic vessels varies throughout the body; sources include local splanchnopleuric mesenchyme condensing around endothelial networks and, within and around the vertebrae and muscles of the back and the descending aorta, from local somites ( ).

Following a period of proliferation, clusters of myoblasts become elongated in the same orientation. Dense bodies, associated with actin and cytoskeletal filaments, appear in the cytoplasm, and the surface membrane starts to acquire its specialized features, i.e. caveolae, adherens junctions and gap junctions. Cytoskeletal filaments extend to insert into the submembraneous dense plaques and cytoplasmic dense bodies. Thick filaments are seen a few days after the first appearance of thin filaments and intermediate filaments, and from this time the cells are able to contract. During development, dense bodies increase in number and further elements of the cytoskeleton are added. In addition to synthesizing the cytoskeleton and contractile apparatus, the differentiating cells express and secrete components of the extracellular matrix.

In a developing smooth muscle, all the cells express characteristics of the same stage of differentiation and there are no successive waves of differentiation. From its earliest appearance to maturity, a smooth muscle increases several hundred-fold in mass, partly by a 2–4-fold increase in the size of individual cells, but mainly by a very large increase in cell number. Growth occurs by division of cells in every part of the muscle, not just at its surface or ends. Mitosis occurs in cells in which differentiation is already well advanced, as evidenced by the presence of myofilaments and membrane specializations. Mitotic smooth muscle cells may be found at any stage of life but their numbers peak before birth, at a time that differs for different muscles; they are rare in the adult unless the tissue is stimulated to hypertrophy (as in the pregnant uterus) or to repair. The ability of mature cells to undergo mitosis therefore differs between the three major types of muscle: skeletal muscle cells cannot divide at all after differentiation; cardiac muscle cells can divide but only before birth; and smooth muscle cells appear to remain capable of division throughout life.

During the early stages of development, smooth muscle expresses embryonic and non-muscle isoforms of myosin. The proportions of these isoforms decrease progressively. Initially, SM-1 is the dominant or exclusive smooth muscle heavy chain isoform and the SM-2 isoform becomes more established later. For a review of the development of vascular smooth muscle, see .

Smooth muscle remodelling in disease

The ability of smooth muscle cells to divide and change phenotype throughout life means that smooth muscle has significant plasticity and can adapt to changing needs and stimuli, e.g. in the walls of the uterus during pregnancy. This can, however, have detrimental consequences in disease.

Sustained stress (physical or oxidative), tissue damage, inflammatory mediators and other stimuli can promote enhanced growth, apoptosis (programmed cell death, p. 27 ) and switching to a more secretory phenotype (see above). Increased mediator release by the more secretory phenotype can potentiate such changes and attract inflammatory cells, resulting in a positive feedback loop. Chronic disease and inflammation can therefore lead to extensive smooth muscle remodelling, a major contributing factor to, for example, chronic asthma and pulmonary hypertension, which significantly worsens conditions ( , ). Peripheral vascular remodelling may also occur in essential hypertension and diabetes.

General organization

Cells of peripheral blood, suspended in plasma, circulate through the body in the blood vascular system. Fluid and solutes exchange between the plasma and interstitium across capillaries and small venules. Excess interstitial fluid from peripheral tissues returns to the blood vascular system via the lymphatic system, which also provides a channel for the migration of leukocytes and the absorption of certain nutrients from the gut.

The cardiovascular system carries nutrients, oxygen, hormones, etc. throughout the body and the blood redistributes and disperses heat. As a consequence of the hydrostatic pressure, the system also has mechanical effects, such as maintaining tissue turgidity. Blood circulates within a system made up of the heart, the central pump and main motor of the system; arteries, which lead away from the heart and carry the blood to the periphery; and veins, which return the blood to the heart. The heart is essentially a pair of muscular pumps, one feeding the pulmonary circulation, which is responsible for gas exchange in the lungs and has a low hydrostatic pressure, and the other feeding the systemic circulation, which has a high hydrostatic pressure and serves the rest of the body. With limited exceptions, both circulations form a closed system of tubes, so that blood per se does not usually leave the circulation.

From the centre to the periphery, the vascular tree shows three main modifications. The arteries increase in number by repeated bifurcation and by sending out side branches, in both the systemic and the pulmonary circulation. For example, the aorta, which carries blood from the heart to the systemic circulation, gives rise to about 4 ×10 ⁶ arterioles and four times as many capillaries. The arteries also decrease in diameter, although not to the same extent as their increase in number, so that a hypothetical cross-section of all the vessels will show an increase in total area with increasing distance from the heart. At its emergence from the heart, the aorta of an adult man has an outer diameter of approximately 30 mm (cross-sectional area of nearly 7 cm ² ). The diameter decreases along the arterial tree until it is as little as 10 μm in arterioles (each with a cross-sectional area of about 80 μm ² ). However, given the enormous number of arterioles, the total cross-sectional area at this level is approximately 150 cm ² , more than 200 times that of the aorta. As a result, blood flow is faster near the heart than at the periphery.

The walls of arteries decrease in thickness towards the periphery, although this is not as substantial as the reduction in vessel diameter. Consequently, in the smallest arteries (arterioles), the thickness of the wall represents about half the outer radius of the vessel, whereas in a large vessel it represents between one-fifteenth and one-fifth, e.g. in the thoracic aorta the radius is approximately 17 mm and the wall thickness 1.1 mm.

Venules, which return blood from the capillaries, converge on each other, forming a progressively smaller number of veins of increasingly large size. As with arteries, the hypothetical total cross-sectional area of all veins at a given level reduces nearer to the heart. Eventually, only the two largest veins, the superior and inferior venae cavae, open into the heart from the systemic circulation. A similar pattern is found in the pulmonary circulation but here the vascular loop is shorter and has fewer branch points, and consequently, the number of vessels is smaller than in the systemic circulation. The total end-to-end length of the vascular network in a typical adult is twice the circumference of the earth.

Large arteries, such as the thoracic aorta and subclavian, axillary, femoral and popliteal arteries, lie close to a single vein that drains the same territory as that supplied by the artery. Other arteries are usually flanked by two veins, satellite veins (venae comitantes), which lie on either side of the artery and have numerous cross-connections; the whole is enclosed in a single connective tissue sheath. The artery and the two satellite veins are often associated with a nerve, and when they are surrounded by a common connective tissue sheath they form a neurovascular bundle.

The close association between the larger arteries and veins in the limbs allows counterflow exchange of heat. This mechanism promotes heat transfer from arterial to venous blood and thus helps to preserve body heat. Counterflow heat exchange systems are found in certain organs, e.g. in the testis, where the pampiniform plexus of veins surrounds the testicular artery (this arrangement not only conserves body heat, but also maintains the temperature of the testis below average body temperature). Counterflow exchange mechanisms are found in the microcirculation, as in the vasa recta in the renal medulla. Here, countercurrent exchange retains solutes at a high concentration in the medullary interstitium, with efferent venous blood transferring solutes to the afferent arterial supply; this mechanism is essential for concentration of the urine.

Arteries and veins are named primarily according to their anatomical position. In functional terms, four main classes of vessel are described: conducting and distributing vessels (large arteries), resistance vessels (small arteries but mainly arterioles), exchange vessels (capillaries, sinusoids and small venules) and capacitance vessels (veins). Structurally, arteries can also be divided into elastic and muscular types. Although muscle cells and elastic tissue are present in all arteries, the relative amount of elastic material is greatest in the largest vessels, whereas the relative amount of smooth muscle increases progressively towards the smallest arteries.

The large conducting arteries that arise from the heart, together with their main branches, are characterized by the predominantly elastic properties of their walls. Distributing vessels are smaller arteries supplying the individual organs, and their walls are characterized by a well-developed muscular component. Resistance vessels include the smallest arteries and arterioles, and are highly muscularized. They provide the major part of peripheral resistance to blood flow and so cause the largest drop in blood pressure before the blood flows into the tissue capillary beds.

Capillaries, sinusoids and small (postcapillary) venules are collectively termed exchange vessels. Their thin walls allow exchange between blood and the interstitial fluid that surrounds all cells: this is the essential function of a circulatory system. Arterioles, capillaries and venules constitute the microvasculature, the structural basis of the microcirculation.

Larger venules and veins form an extensive but variable, large-volume, low-pressure system of vessels conveying blood back to the heart. Their high capacitance is due to the significant distensibility (compliance) of their walls, so that the content of blood is high even at low pressures. Veins contain the greatest proportion of blood, reflecting their large relative volume.

Blood from the gastrointestinal tract (with the exception of the lower part of the anal canal) and from the spleen, pancreas and gallbladder drains to the liver via the portal vein. The portal vein ramifies within the substance of the liver like an artery and ends in the hepatic sinusoids. These drain into the hepatic veins, which in turn drain into the inferior vena cava. Blood supplying the abdominal organs thus passes through two sets of capillaries before it returns to the heart. The first provides the organs with oxygenated blood, and the second carries deoxygenated blood, rich in absorption products from the intestine, through the liver parenchyma. A venous portal circulation also connects the median eminence and infundibulum of the hypothalamus with the adenohypophysis. In essence, a venous portal system is a capillary network that lies between two veins, instead of between an artery and a vein, which is the more usual arrangement in the circulation. A capillary network may also be interposed between two arteries, e.g. in the renal glomeruli, where the glomerular capillary bed lies between afferent and efferent arterioles. This maintains a relatively high-pressure system, which is important for renal filtration.

A parallel circulatory system is provided by the lymphatic vessels and lymph nodes. Lymphatic vessels originate in peripheral tissues as blind-ended endothelial tubes that collect excess fluid from the interstitial spaces between cells and conduct it as lymph. Lymph is returned to the blood vascular system via lymphatic vessels, which converge on the large veins in the root of the neck.

Certain pathologies of the cardiovascular and lymphatic systems are described below; for information on vascular tumours, see . The development of blood vessels is described in Chapter 13 .

Large elastic arteries

The aorta and its largest branches (brachiocephalic, common carotid, subclavian and common iliac arteries) are large elastic arteries that conduct blood to the medium-sized distributing arteries.

The intima is made of an endothelium, resting on a basal lamina, and a subendothelial connective tissue layer. The endothelial cells are flat, elongated and polygonal in outline, with their long axes parallel to the direction of blood flow (see Fig. 6.17 ). The subendothelial layer is well developed, contains elastic fibres and type I collagen fibrils, fibroblasts and small, smooth muscle-like myointimal cells. The latter accumulate lipid with age, and in an extreme form this contributes to atherosclerosis (see below). Thickening of the intima progresses with age and is more marked in the distal than in the proximal segment of the aorta.

A prominent internal elastic lamina, sometimes split, lies between intima and media. This lamina is smooth, measures about 1 μm in thickness, and, with the elastic lamellae of the media, is stretched under the effect of systolic pressure, recoiling elastically in diastole. Elastic arteries can thus sustain continuous blood flow despite the pulsatile cardiac output, and smooth out the cyclical pressure wave. The media has a markedly layered structure, in which fenestrated layers of elastin (elastic lamellae) alternate with interlamellar smooth muscle cells ( Fig. 6.6 ), collagen and fine elastic fibres. The arrangement is very regular, such that each elastic lamella and adjacent interlamellar zone is regarded as a ‘lamellar unit’ of the media. In the human aorta there are approximately 52 lamellar units, measuring about 11 μm in thickness. Number and thickness of lamellar units increases during postnatal development, from 40 at birth.

The adventitia is well developed. In addition to collagen and elastic fibres, it contains flattened fibroblasts with extremely long, thin processes, macrophages and mast cells, nerve bundles and lymphatic vessels. The vasa vasorum is usually confined to the adventitia.

Muscular arteries

Muscular arteries are characterized by the predominance of smooth muscle in the media ( Fig. 6.7 ). The intima consists of an endothelium, similar to that of elastic arteries, which rests on a basal lamina and subendothelial connective tissue. The internal elastic lamina (see Fig. 6.7 ; Fig. 6.8 ) is a distinct, thin layer, sometimes duplicated and occasionally absent. It is thrown into wavy folds as a result of contraction of smooth muscle in the media. Some 75% of the mass of the media consists of smooth muscle cells that run spirally or circumferentially around the vessel wall. The relative amount of extracellular matrix is therefore less than in large arteries, although fine elastic fibres that run mainly parallel to the muscle cells are present. An external elastic lamina, composed of sheets of elastic fibres, forms a less compact layer than the internal lamina, and separates the media from the adventitia in larger muscular arteries. The adventitia is made of fibroelastic connective tissue, and can be as thick as the media in the smaller arteries. The inner part of the adventitia contains more elastic than collagen fibres.

Arterioles

The endothelial cells in arterioles are smaller than in large arteries, but their nuclear region is thicker and often projects markedly into the lumen ( Figs 6.9 – 6.10 ). The nuclei are elongated and orientated parallel to the vessel length, as is the long axis of the cell. The basal surface of the endothelium contacts a basal lamina, but an internal elastic lamina is either absent or highly fenestrated and traversed by cytoplasmic processes of muscle or endothelial cells. The muscle cells are larger in cytoplasmic volume than those in the walls of large arteries and form a layer one or two cells thick. They are arranged circumferentially and are tightly wound around the endothelium. In the smallest arterioles each cell makes several turns, producing extensive apposition between parts of the same cell. Contraction of the muscle constricts the lumen, and so controls blood flow into the capillary bed; arterioles thus act functionally as precapillary sphincters, even though the absence of an anatomically delineated sphincter means that the term is no longer commonly used. Contraction of arterioles is primarily regulated by local vasoactive and metabolic factors, but can also be controlled by central mechanisms.

Arterioles are usually densely innervated by sympathetic fibres, via small bundles of varicose axons packed with transmitter vesicles, mostly of the adrenergic type. The distance between axolemma and muscle cell membrane can be as little as 50–100 nm and the gap is occupied only by a basal lamina. Autonomic neuromuscular junctions are very common in arterioles. Arteriolar adventitia is very thin.

Capillaries

The capillary wall ( Fig. 6.11 ) is formed by an endothelium and its basal lamina, plus a few isolated pericytes. Capillaries are the vessels closest to the tissue they supply and their wall constitutes a minimal barrier between blood and the surrounding tissues. Capillary structure varies in different locations. Capillaries measure 4–8 μm in diameter (much more in the case of sinusoids) and are hundreds of microns long. Their lumen is just large enough to admit the passage of single blood cells, usually with considerable deformation. Typically a single endothelial cell forms the wall of a capillary, and there are junctional complexes between extensions of the same cell.

Endothelial cells are joined by tight junctions (occluding junctions, zonulae occludentes), forming a diffusion barrier. Capillary permeability varies greatly among tissues and is correlated largely with the type of endothelium. The majority of tissues, including brain, muscle, lung and connective tissues, contain capillaries with a continuous, unbroken layer of endothelium (continuous endothelium). This is impermeable to proteins, although electrolytes can diffuse through the tight junctions, albeit relatively slowly. Their passage is further limited in brain, thymic cortex and testis by particularly tight junctions.

Endothelial cells of some capillaries have fenestrations (pores) through their cytoplasm that facilitate diffusion. Fenestrations are approximately circular and 50–100 nm in diameter, and at their edge the luminal and abluminal membranes of the endothelial cell come into contact. The fenestration itself is usually occupied by a thin, electron-dense diaphragm containing glycoprotein PV-1, which restricts passage of large molecules such as proteins. Fenestrated capillaries occur in intestinal mucosae, endocrine and exocrine glands, and renal glomeruli, where they may lack a diaphragm. Fenestrations are almost invariably present in capillaries that lie close to an epithelium, including the skin.

Sinusoids

Sinusoids are expanded capillaries ( Fig. 6.12 ), and are large and irregular in shape. They have true discontinuities in their walls, allowing intimate contact between blood and the parenchyma. The discontinuities are formed by gaps between fenestrated endothelial cells, such that the sinusoidal lining, and sometimes also the basal lamina, is incomplete. Sinusoids occur in large numbers in the liver (where a basal lamina is completely absent), spleen, bone marrow, adenohypophysis (see Fig. 6.12 ) and suprarenal medulla.