Blood Vessels Vascular pathology is responsible for more morbidity and mortality than any other category of human disease. Although the most clinically significant lesions involve arteries, venous disorders are not inconsequential. Two principal mechanisms underlie vascular disease: • Narrowing (stenosis) or complete obstruction of vessel lumens, either progressively (e.g., by atherosclerosis) or precipitously (e.g., by thrombosis or embolism) • Weakening of vessel walls, leading to dilation or rupture To better appreciate the pathogenesis of vascular disorders, it is important to first understand the normal vessel structure and function. VASCULAR STRUCTURE AND FUNCTION The general architecture and cellular composition of blood vessels are comparable throughout the cardiovascular system. However, structural specializations that reflect distinct functional roles characterize specific kinds of vessels (Fig. 11.1). For example, arterial walls are thicker than corresponding veins at the same level of branching to accommodate pulsatile flow and higher blood pressures. Arterial wall thickness gradually diminishes as the vessels become smaller, but the ratio of wall thickness to lumen diameter increases, allowing these muscular vessels to exert control over blood flow and pressure. Many disorders of the vasculature affect only particular types of vessels and thus have characteristic anatomic distributions. Thus atherosclerosis affects mainly elastic and muscular arteries, hypertension affects small muscular arteries and arterioles, and different varieties of vasculitis characteristically involve only vessels of a certain caliber. The basic constituents of the walls of blood vessels are endothelial cells (ECs) and smooth muscle cells (SMCs), admixed with a variety of extracellular matrix (ECM) including elastin, collagen, and glycosaminoglycans. The relative amount and configuration of the basic constituents differ along the vasculature owing to local adaptations to mechanical or metabolic needs. In arteries and veins, these constituents are organized into three concentric layers—intima, media, and adventitia, which are anatomically more distinct in the arteries. • The intima normally consists of a single layer of ECs attached to a basement membrane with a thin underlying LOW PRESSURE HIGH PRESSURE Elastic artery Muscular artery Lumen Aorta Adventitia Intima Media Large vein Internal elastic lamina Adventitia Muscular artery Lumen Adventitia Arteriole Venule Pericytes Media Intima Post-capillary venule Media Intima Medium vein BLOOD PRESSURE CONTROL Capillary Endothelial cell Intima Media Adventitia GAS AND NUTRIENT EXCHANGE Figure 11.1 Regional specializations of the vasculature. Although the basic organization of the vasculature is constant, the thickness and composition of the various layers differs according to hemodynamic forces and tissue requirements. Thus, the aorta and other elastic arteries have substantial elastic tissue to accommodate high pulsatile forces, with the capacity to recoil and transmit energy into forward blood flow. These vessels have lamellar units that are comprised of repetitions of a layer of elastic fibers, a smooth muscle cell, and intervening extracellular matrix. Purely muscular arteries have elastic fibers only at the intersection of the intima and media or media and adventitia. In comparison, the venous system has relatively poorly developed thinner medial layers that permit greater capacitance, and the capillary wall permits ready diffusion of oxygen and nutrients because it is comprised only of an endothelial cell and sparse encircling pericytes. The different structure and functional attributes also influence the disorders that can affect the various parts of the vascular tree. Thus, loss of aortic elastic tissue will result in aneurysm, while stasis in a dilated venous bed can result in thrombosis. layer of ECM; the intima is demarcated from the media by the internal elastic lamina. • The media of elastic arteries (e.g., the aorta) are arranged in layers of lamellar units of elastin fibers and SMCs akin to tree rings. This high elastin content allows these vessels to expand during systole and recoil during diastole—functionally propelling blood toward the tissues. With aging and the loss of elasticity, the aorta and larger arteries become less compliant; besides transmitting higher pressures into distal tissues, the arteries of older individuals often become progressively tortuous and dilated (ectatic). • In muscular arteries, the media is composed predominantly of circumferentially oriented SMCs. Arteriolar SMC contraction (vasoconstriction) or relaxation (vasodilation) is regulated by inputs from the autonomic nervous system and local metabolic factors. • Arterioles are the principal points of physiologic resistance to blood flow. Since the resistance to fluid flow is inversely proportional to the fourth power of the diameter (i.e., halving the diameter increases resistance 16-fold), small decreases in the lumen size of arterioles caused by structural changes or vasoconstriction can have profound effects on blood pressure. • The adventitia lies external to the media and in many arteries is separated from the media by a well-defined external elastic lamina. The adventitia consists of loose connective tissue and can also contain nerve fibers. Diffusion of oxygen and nutrients from the lumen is adequate to sustain thin-walled vessels and the innermost SMCs of all vessels. In large- and medium-sized vessels, however, small arterioles within the adventitia (called vasa vasorum—literally, “vessels of the vessels”) perfuse the outer half to two-thirds of the media. As already alluded to, arteries are divided into three types based on their size and structural features: (1) large or elastic arteries including the aorta, the major branches of the aorta (innominate, subclavian, common carotid, and iliac), and pulmonary arteries; (2) medium-sized or muscular arteries comprising smaller branches of the aorta (e.g., coronary and renal arteries); and (3) small arteries (≤2 mm in diameter) and arterioles (20 to 100 µm in diameter) within tissues and organs. Capillaries are slightly smaller (5 µm) than the diameter of a red blood cell (7 to 8 µm); they have an EC lining but no media, although variable numbers of pericytes, cells that resemble SMCs, typically lie just deep to the endothelium. Collectively, capillaries have a huge cross-sectional area and also have a relatively low flow rate. The combination of thin walls and slow flow makes capillaries ideally suited for the exchange of diffusible substances between blood and tissues. Because functionally useful oxygen diffusion is limited to a distance of only approximately 100 µm, the capillary network of most tissues is very rich. Tissues with high metabolic rates such as myocardium and brain have the highest density of capillaries. Blood from capillary beds flows into postcapillary venules and then sequentially through collecting venules and small, medium, and large veins. In most forms of inflammation, vascular leakage and leukocyte exudation occur preferentially from postcapillary venules (Chapter 3). Relative to arteries at the same level of branching, veins have larger diameters, larger lumens, and thinner and less well-organized walls (see Fig. 11.1). These structural features augment the capacitance of the venous side of the circulation, which on average contains about two-thirds of total blood volume. Reverse flow (due to gravity) is prevented in the extremities by venous valves. Lymphatics are thin-walled, endothelium-lined channels that drain lymph (water, electrolytes, glucose, fat, proteins, and inflammatory cells) from the interstitium of tissues, eventually reconnecting with the blood stream via the thoracic duct. Lymphatics transport interstitial fluid and inflammatory cells from the periphery to lymph nodes, thereby facilitating antigen presentation and cell activation in the nodal tissues—and enabling continuous monitoring of peripheral tissues for infection. This can be a double-edged sword, however, as these channels can also disseminate disease by transporting microbes or tumor cells to distant sites. KEY CONCEPTS VASCULAR STRUCTURE AND FUNCTION • All vessels except capillaries share a general three-layered architecture consisting of an endothelial-lined intima, surrounding smooth muscle media, and supportive adventitia. • The SMCs and ECM of arteries, veins, and capillaries vary according to hemodynamic demands (e.g., pressure, pulsatility) and functional requirements. • The specific composition of the vessel wall at any given site within the vascular tree influences the nature and consequences of pathologic injuries. VASCULAR ANOMALIES Although rarely symptomatic, anatomic variants of the usual vascular supply are important to recognize, as the failure to do so may lead to surgical complications and impede attempted therapeutic interventions (e.g., placement of coronary artery stents). Among the other congenital vascular anomalies, four are particularly significant, although not necessarily common. • Developmental or berry aneurysms occur in cerebral vessels; when ruptured, these can cause fatal intracerebral hemorrhage (Chapter 28). • Arteriovenous fistulas are direct connections (usually small) between arteries and veins that bypass capillaries. They occur most commonly as developmental defects but can also result from rupture of an arterial aneurysm into the adjacent vein, from penetrating injuries that pierce arteries and veins, or from inflammatory necrosis of adjacent vessels. Surgically generated arteriovenous fistulas provide vascular access for chronic hemodialysis. Like berry aneurysms, arteriovenous fistulas can rupture. Large or multiple arteriovenous fistulas become clinically significant by shunting blood from the arterial to the venous circulations, forcing the heart to pump additional volume and leading to high-output cardiac failure. • Fibromuscular dysplasia is a focal irregular thickening in medium and large muscular arteries including renal, carotid, splanchnic, and vertebral vessels. The cause is unknown. Segments of the vessel wall are focally thickened by a combination of medial and intimal hyperplasia and fibrosis, resulting in luminal stenosis. In the renal arteries, it can be a cause of renovascular hypertension (Chapter 20). Immediately adjacent vessel segments can have markedly attenuated media (on angiography the vessels are said to have a “string of beads” appearance) leading to vascular outpouchings (aneurysms) that can rupture. • Anomalous coronary artery origin occurs from a developmental anomaly in which both coronary arteries arise over the same coronary cusp of the aortic valve. Although many of these anomalies are benign, when a coronary vessel passes between the aorta and pulmonary artery it can be squeezed, for example, during exercise, limiting blood flow and resulting in sudden death. VASCULAR WALL RESPONSE TO INJURY The integrated functioning of ECs and SMCs impacts physiologic and pathophysiologic responses to hemodynamic and biochemical stimuli. Their function (and dysfunction) are described briefly, followed by discussion of specific vascular disorders. ECs form a specialized simple squamous epithelium lining for blood vessels. Although ECs throughout the vascular tree share many attributes, populations that line different portions of the vascular tree (large vessels vs. capillaries, arteries vs. veins) have distinct gene expression profiles, behaviors, and morphologic appearances. Thus ECs in liver sinusoids or in renal glomeruli are fenestrated (they have holes, presumably to facilitate filtration), while central nervous system ECs (along with the associated perivascular cells) create an impermeable blood-brain barrier. ECs are versatile multifunctional cells with a wealth of synthetic and metabolic properties. In the normal state they have several constitutive activities that are critical for vessel homeostasis and circulatory function (Table 11.1). Unless injured or otherwise activated, ECs have a nonthrombogenic surface that maintains blood in a fluid state (Chapter 4). They also modulate medial SMC tone (thereby influencing Table 11.1 Endothelial Cell Properties and Functions Property/Function Mediators/Products Maintenance of permeability barrier Elaboration of anticoagulant, antithrombotic, and fibrinolytic regulators Prostacyclin Thrombomodulin Heparin-like molecules Plasminogen activator Elaboration of prothrombotic molecules Von Willebrand factor Tissue factor Plasminogen activator inhibitor Production of extracellular matrix Collagen, proteoglycans Modulation of blood flow and vascular reactivity Vasoconstrictors: endothelin, ACE Vasodilators: NO, prostacyclin Regulation of inflammation and immunity IL-1, IL-6, chemokines Adhesion molecules: VCAM-1, ICAM, E-selectin, P-selectin Histocompatibility antigens Regulation of cell growth Growth stimulators: PDGF, CSF, FGF Growth inhibitors: heparin, TGF-β ACE, Angiotensin-converting enzyme; CSF, colony-stimulating factor; FGF, fibroblast growth factor; ICAM, intercellular adhesion molecule; IL, interleukin; LDL, low-density lipoprotein; NO, nitric oxide; PDGF, platelet-derived growth factor; TGF-β, transforming growth factor-β; VCAM, vascular cell adhesion molecule. vascular resistance); metabolize hormones such as angiotensin; regulate inflammation; and affect the growth of other cell types, particularly SMCs. Although interendothelial junctions are largely impermeable in normal vessels, vasoactive agents (e.g., histamine) cause contraction of ECs and allow the rapid egress of fluids, electrolytes, and protein; in inflammation, even leukocytes can slip between adjacent ECs (Chapter 3). ECs can respond to various stimuli by adjusting their steady-state (constitutive) functions and by expressing newly acquired (inducible) properties—a process termed endothelial activation (Fig. 11.2). There are numerous inducers of endothelial activation including cytokines and bacterial products, which elicit inflammation and, in severe cases, can promote septic shock (Chapter 4). Additional activators include hemodynamic stresses and lipid products that are critical to the pathogenesis of atherosclerosis (see later) and advanced glycation end-products that are important in the pathogenic sequelae of diabetes (Chapter 24). Viruses, complement components, and hypoxia also activate ECs. Activated ECs, in turn, express adhesion molecules (Chapter 3) and produce cytokines, chemokines, growth factors, vasoactive molecules that result either in vasoconstriction or in vasodilation, induction of major histocompatibility complex molecules, procoagulant and anticoagulant factors, and a variety of other biologically active products. ECs influence the vasoreactivity of the underlying SMCs through the production of both vasodilating (relaxing) factors (e.g., nitric oxide [NO]) and vasoconstrictive factors (e.g., endothelin). Normal EC function is characterized by a balance of these responses. Endothelial dysfunction refers to an alteration in endothelial phenotype—seen in many different conditions—that is often both proinflammatory and prothrombogenic. It is responsible, at least in part, for the initiation of thrombus formation, atherosclerosis, and the vascular lesions of hypertension and other disorders. Certain forms of endothelial dysfunction are rapid in onset (within minutes), reversible, and independent of new protein synthesis (e.g., EC contraction induced by histamine and other vasoactive mediators that cause gaps in venular endothelium (Chapter 3). Other changes, such as the upregulation of adhesion molecules, involve alterations in gene expression and protein synthesis and may require hours or even days to develop. Vascular SMCs are the predominant cellular element of the vascular media, playing important roles in normal vascular repair and pathologic processes such as atherosclerosis. SMCs have the capacity to proliferate when appropriately stimulated; they can also synthesize collagen, elastin, and proteoglycans and elaborate growth factors and cytokines. SMCs are also responsible for the vasoconstriction or dilation that occurs in response to physiologic or pharmacologic stimuli. Intimal Thickening: A Stereotyped Response to Vascular Injury Vascular injury associated with EC dysfunction or loss stimulates SMC recruitment and proliferation and associated ECM synthesis; the result is intimal thickening that can compromise vascular flow. Healing of injured vessels is analogous to the healing process that occurs in any other damaged tissue (Chapter 3) but has a somewhat unique outcome because the process impacts downstream blood flow. ECs involved in repair can migrate from adjacent uninjured areas into denuded areas or can derive from Normotension Laminar flow Growth factors (e.g., VEGF) Basal state Non-adhesive, nonthrombogenic surface Endothelium Turbulent flow Hypertension Cytokines Complement Bacterial products Lipid products Advanced glycation end-products Hypoxia, acidosis Viruses Cigarette smoke Increased expression of procoagulants, adhesion molecules, and proinflammatory factors Altered expression of chemokines, cytokines, and growth factors “Activated” state Figure 11.2 Basal and activated endothelial cell states. Normal blood pressure, laminar flow, and stable growth factor levels promote a basal endothelial cell state that maintains a nonthrombotic, nonadhesive surface with appropriate vascular wall smooth muscle tone. Injury or exposure to certain mediators results in endothelial activation, a state where endothelial cells develop a procoagulant surface that can be adhesive for inflammatory cells and express factors that cause smooth muscle contraction and/or proliferation and matrix synthesis. VEGF, Vascular endothelial growth factor.