General characteristics of the cardiovascular system

The cardiovascular system is a continuous, completely closed system of endothelial tubes. The general purpose of the cardiovascular system is the perfusion of capillary beds permeating all organs with fresh blood over a narrow range of hydrostatic pressures. Local functional demands determine the structural nature of the wall surrounding the endothelial tubes.

The circulation is divided into the systemic or peripheral circulation and the pulmonary circulation.

Arteries transport blood under high pressure and their muscular walls are thick (Figure 12-1). The veins are conduits for transport of the blood from tissues back to the heart. The pressure in the venous system is very low and the walls of the veins are thin.

Figure 12-1 Blood pressure and vascular anatomy

There are variations in blood pressure in various parts of the cardiovascular system (see Figure 12-1). Because the heart pumps blood continuously in a pulsatile fashion into the aorta, the pressure in the aorta is high (about 100 mm Hg) and the arterial pressure fluctuates between a systolic level of 120 mm Hg and a diastolic level of 80 mm Hg.

As the blood flows through the systemic circulation, its pressure reaches the lowest value (0 mm Hg) when it returns to the right atrium of the heart through the terminal vena cava. In the capillaries, the pressure is about 35 mm Hg at the arteriolar end and lower (10 mm Hg) at the venous end. Although the pressure in the pulmonary arteries is pulsatile, as in the aorta, the systolic pressure is less (about 25 mm Hg), and the diastolic pressure is 8 mm Hg. The pressure in the pulmonary capillaries is only 7 mm Hg, as compared with an average pressure of 17 mm Hg in the capillary bed of the systemic circulation.

Conductive system of the heart

The heart has two specialized conductive systems:

Figure 12-2 Heart: Purkinje fibers

When stretched, cardiac muscle cells of the atrium (atrial cardiocytes) secrete a peptide called atrial natriuretic factor (ANF) (Figure 12-3) that stimulates both diuresis and excretion of sodium in urine (natriuresis) by increasing the glomerular filtration rate. By this mechanism, the blood volume is reduced.

Figure 12-3 Atrial natriuretic factor

Histologically (see Figure 7-18 in Chapter 7, Muscle Tissue), individual cardiac muscle cells have a central nucleus and are linked to each other by intercalated disks. The presence of gap junctions in the longitudinal segment of the intercalated disks between connected cardiac muscle cells allows free diffusion of ions and the rapid spread of the action potential from cell to cell. The electrical resistance is low because gap junctions bypass the transverse components of the intercalated disk (fasciae adherentes and desmosomes).

Differences between cardiac muscle fibers and Purkinje fibers

The Purkinje fibers lie beneath the endocardium lining the two sides of the interventricular septum (see Figure 12-2). They can be distinguished from cardiac muscle fibers because they contain a reduced number of myofibrils located at the periphery of the fiber and the diameter of the fiber is larger. In addition, they give a positive reaction for acetylcholinesterase, and they contain abundant glycogen. Purkinje fibers lose these specific characteristics when they merge with cardiac muscle fibers. Like cardiac muscle fibers, Purkinje fibers are striated and are linked to each other by atypical intercalated disks.

Large elastic arteries are conducting vessels

The aorta and its largest branches (the brachiocephalic, common carotid, subclavian, and common iliac arteries) are elastic arteries (Figure 12-5). They are conducting arteries because they conduct blood from the heart to the medium-sized distributing arteries.

Figure 12-5 Structure of an elastic artery (aorta)

Large elastic arteries have two major characteristics: (1) They receive blood from the heart under high pressure. (2) They keep blood circulating continuously while the heart is pumping intermittently. Because they distend during systole and recoil during diastole, elastic arteries can sustain a continuous blood flow despite the intermittent pumping action of the heart.

The tunica intima of the elastic arteries consists of the endothelium and the subendothelial connective tissue.

Large amounts of fenestrated elastic sheaths are found in the tunica media, with bundles of smooth muscle cells permeating the narrow gaps between the elastic lamellae. Collagen fibers are present in all tunics, but especially in the adventitia. We have seen in Chapter 4, Connective Tissue, that smooth muscle cells can synthesize both elastic and collagen fibers. Blood vessels (vasa vasorum), nerves (nervi vasorum), and lymphatics can be recognized in the tunica adventitia of large elastic arteries.

Clinical significance: Aortic aneurysms

The two major types of aortic aneurysms are the syphilitic aneurysm (relatively rare because syphilis is no longer common) and the abdominal aneurysm. The latter is caused by a weakening of the aortic wall produced by atherosclerosis (see Figure 12-14). Aortic aneurysms generate murmurs caused by blood turbulence in the dilated aortic segment. A severe complication is rupture of the aneurysm followed by immediate death.

Marfan syndrome (see Chapter 4, Connective Tissue) is an autosomal dominant defect associated with aortic dissecting aneurysm and skeletal and ocular abnormalities due to mutations in the fibrillin 1 gene. Fibrillins are major components of the elastic fibers found in the aorta, periosteum, and suspensory ligament of the lens.

Medium-sized muscular arteries are distributing vessels

There is a gradual transition from large arteries, to medium-sized arteries, to small arteries and arterioles. Medium-sized arteries are distributing vessels, allowing a selective distribution of blood to different organs in response to functional needs. Examples of medium-sized arteries include the radial, tibial, popliteal, axillary, splenic, mesenteric, and intercostal arteries. The diameter of medium-sized muscular arteries is about 3 mm or greater.

The tunica intima consists of three layers: (1) the endothelium, (2) the sub-endothelium, and (3) the internal elastic lamina (see Figure 12-4).

The internal elastic lamina is a fenestrated band of elastic fibers that often shows folds in sections of fixed tissue owing to contraction of the smooth muscle cell layer (tunica media).

The tunica media shows a significant reduction in elastic components and an increase in smooth muscle fibers. In the larger vessels of this group, a fenestrated external elastic lamina can be seen at the junction of the tunica media and the adventitia.

Arterioles are resistance vessels

Arterioles are the final branches of the arterial system. Arterioles regulate the distribution of blood to different capillary beds by vasoconstriction and vasodilation in localized regions. Partial contraction (known as tone) of the vascular smooth muscle exists in arterioles. Arterioles are structurally adapted for vasoconstriction and vasodilation because their walls contain circularly arranged smooth muscle fibers. Arterioles are regarded as resistance vessels and are the major determinants of systemic blood pressure (Figure 12-6).

Figure 12-6 Arterioles: Resistance vessels

The diameter of arterioles and small arteries ranges from 20 to 130 μm. Because the lumen is small, these blood vessels can be closed down to generate high resistance to blood flow. The tunica intima has an endothelium, subendothelium, and internal elastic lamina. The tunica media consists of two to five concentric layers of smooth muscle cells. The tunica adventitia, or tunica externa, contains slight collagenous tissue, binding the vessel to its surroundings.

The segment beyond the arteriole proper is the metarteriole, the terminal branch of the arterial system. It consists of one layer of muscle cells, often discontinuous, and represents an important local regulator of blood flow.

Capillaries are exchange vessels

Capillaries are extremely thin tubes formed by a single layer of highly permeable endothelial cells surrounded by a basal lamina. The diameter range of a capillary is about 5 to 10 μm, large enough to accommodate one red blood cell, and thin enough (0.5 μm) for gas diffusion.

The microvascular bed, the site of the microcirculation (Figure 12-7), is composed of the terminal arteriole (and metarteriole), the capillary bed, and the postcapillary venules. The capillary bed consists of slightly large capillaries (called preferential or thoroughfare channels), where blood flow is continuous, and small capillaries, called the true capillaries, where blood flow is intermittent.

Figure 12-7 Microcirculation: Components and function

The amount of blood entering the microvascular bed is regulated by the contraction of smooth muscle fibers of the precapillary sphincters located where true capillaries arise from the arteriole or metarteriole. The capillary circulation can be bypassed by channels (through channels) connecting terminal arterioles to postcapillary venules.

When functional demands decrease, most precapillary sphincters are closed, forcing the flow of blood into thoroughfare channels. Arteriovenous shunts, or anastomoses, are direct connections between arterioles and postcapillary venules and bypass the microvascular bed.

The three-dimensional design of the microvasculature varies from organ to organ. The local conditions of the tissues (concentration of nutrients and metabolites and other substances) can control local blood flow in small portions of a tissue area.

Three types of capillaries: Continuous, fenestrated, and discontinuous

Three morphologic types of capillaries are recognized (Figures 12-8 and 12-9): continuous, fenestrated, and discontinuous (sinusoids).

Figure 12-8 Structure of capillaries

Figure 12-9 Types of capillaries

Continuous capillaries are lined by a complete simple squamous endothelium and a basal lamina. Pericytes can occur between the endothelium and the basal lamina. Pericytes are undifferentiated cells that resemble modified smooth muscle cells and are distributed at random intervals in close contact with the basal lamina. Endothelial cells are linked by tight junctions and transport fluids and solutes by caveolae and pinocytotic vesicles. Continuous capillaries occur in the brain, muscle, skin, thymus, and lungs.

Fenestrated capillaries have pores, or fenestrae, with or without diaphragms. Fenestrated capillaries with a diaphragm are found in intestines, endocrine glands, and around kidney tubules. Fenestrated capillaries without a diaphragm are characteristic of the renal glomerulus. In this particular case, the basal lamina constitutes an important permeability barrier, as we will analyze in Chapter 14, Urinary System.

Discontinuous capillaries are characterized by an incomplete endothelial lining and basal lamina, with gaps or holes between and within endothelial cells. Discontinuous capillaries and sinusoids are found where an intimate relation is needed between blood and parenchyma (for example, in the liver and spleen).

Veins are capacitance, or reservoir, vessels

The venous system starts at the end of the capillary bed with a postcapillary venule that structurally resembles continuous capillaries but with a wider lumen. Postcapillary venules, the preferred site of migration of blood cells into tissues by a mechanism called diapedesis (Greek dia, through; pedan, to leap), are tubes of endothelial cells supported by a basal lamina and an adventitia of collagen fibers and fibroblasts.

In lymphatic tissues, the endothelial cells are taller. High endothelial venules are associated with the mechanism of homing of lymphocytes in lymphoid organs (see Chapter 10, Immune-Lymphatic System).

Postcapillary venules converge to form muscular venules, which converge into collecting venules, leading to a series of veins of progressively larger diameter.

Veins have a relatively thin wall in comparison with arteries of the same size (Figure 12-10). The high capacitance of veins is attributable to the distensibility of their wall (compliance vessels) and, therefore, the content of blood is large relative to the volume of the veins. A small increase in the intraluminal pressure results in a large increase in the volume of contained blood.

Figure 12-10 Structure of a vein

Similar to arteries, veins consist of tunics. However, the distinction of a tunica media from a tunica adventitia is often not clear. The lumen is lined by an endothelium and a subjacent basal lamina. A distinct internal elastic lamina is not seen.

The muscular tunica media is thinner than in arteries, and smooth muscle cells have an irregular orientation, approximately circular. A longitudinal orientation is observed in the iliac vein, brachiocephalic vein, superior and inferior venae cavae, portal vein, and renal vein.

The tunica adventitia consists of collagen fibers and fibroblasts with few nerve fibers. In large veins, the vasa vasorum penetrate the wall.

A typical characteristic of veins is the presence of valves to prevent reflux of blood. A valve is a projection into the lumen of the tunica intima, covered by endothelial cells and strengthened by elastic and collagen fibers.

Lymphatic vessels

The functions of the lymphatic vascular system are to (1) conduct immune cells and lymph to lymph nodes, (2) remove excess fluid accumulated in interstitial spaces, and (3) transport chylomicrons, lipid-containing particles, through lacteal lymphatic vessels inside the intestinal villi (see Chapter 16, Lower Digestive Segment). The flow of lymph is under low pressure and unidirectional.

Lymphatic capillaries form networks in tissue spaces and begin as dilated tubes with closed ends (blind tubes) in proximity to blood capillaries. Lymphatic capillaries collect tissue fluid, the lymph. The wall of a lymphatic capillary consists of a single layer of endothelial cells lacking a complete basal lamina (Figure 12-11). Bundles of anchoring filaments associated to the endothelium prevent the lymphatic capillaries from collapsing during changes in interstitial pressure and enable the uptake of soluble tissue components. Lymphatic capillaries can be found in most tissues. Exceptions are cartilage, bone, epithelia, the central nervous system, bone marrow, and placenta.

Figure 12-11 “Blind sac” origin of lymphatic capillaries

The accumulation of fluid in the interstitial space is a normal event of circulation and blind-ended lymphatic capillaries take up the excess fluid. An increase in the intraluminal volume in the lymphatic capillary opens the overlapping cytoplasmic flaps drawing fluid in. When the lymphatic capillary fills, the overlapping flaps, acting as a primary valve opening, close, preventing fluid backflow into the interstitium.

Lymphatic capillaries converge into precollecting lymphatic vessels draining lymph into collecting lymphatic vessels. The collecting vessels are surrounded by smooth muscle cells, which provide intrinsic pumping activity. Movement in the surrounding tissue provides a passive extrinsic pump.

The collecting vessels consist of bulblike segments separated by luminal valves. The sequential contraction of each segment, called lymphangions, propels the unidirectional flow of lymph (see Box 12-A). A collecting lymphatic vessel gives rise to terminal lymphatic vessels in the proximity of a lymph node. These terminal lymphatic vessels branch and become lymphatic afferent vessels, which penetrate the lymph node capsule and release lymph and its contents into the subcapsular sinus. Lymph nodes are distributed along the pathway of the lymph vessels to filter the lymph before reaching the thoracic and right lymphatic ducts. A total of 2 to 3 L of lymph is produced each day.

Lymph is returned to the bloodstream via two main trunks: (1) the large thoracic duct and (2) the smaller right lymphatic duct.

Larger lymphatic vessels have three layers, similar to those of the small veins, but the lumen is larger.

The tunica intima consists of an endothelium and a thin subendothelial layer of connective tissue.

The tunica media contains a few smooth muscle cells in a concentric arrangement separated by collagenous fibers.

The tunica adventitia is connective tissue with fibroelastic fibers.

Like veins, lymphatic vessels have valves, but their number is larger. The structure of the thoracic duct is similar to that of a medium-sized vein, but the muscular tunica media is more prominent.

Clinical significance: Edema

Edema occurs when the volume of interstitial fluid increases and exceeds the drainage capacity of the lymphatics, or lymphatic vessels become blocked. Subcutaneous tissue has the capacity to accumulate interstitial fluid and gives rise to clinical edema (see Box 12-B).

In patients with extensive capillary injury (burns), both intravascular fluid and plasma proteins escape into the interstitial space. Proteins accumulating in the interstitial compartment increase the oncotic pressure, leading to additional fluid loss due to the greater osmotic force outside the capillary bed.

Special capillary arrangements: Glomerulus and portal systems

In general, blood from an arteriole flows into a capillary network and is drained by a venule. There are two specialized capillary systems that depart from this standard arrangement (Figure 12-12): (1) the glomerulus and (2) the portal system.

Figure 12-12 Glomerulus and portal systems

In the kidneys, an afferent arteriole drains into a capillary network called the glomerulus. The glomerular capillaries coalesce to form an efferent arteriole, which branches into another capillary network called the vasa recta. The vasa recta surround the limbs of the loop of Henle and play a significant role in the formation of urine. The glomerulus system is essential for blood filtration in the renal corpuscle (see Chapter 14, Urinary System).

In the portal system, intestinal capillaries are drained by the portal vein to the liver. In the liver, the portal vein branches into venous sinusoids between cords of hepatocytes. Blood flows from the sinusoids into a collecting vein and then back to the heart via the inferior vena cava.

A similar portal system is observed in the hypophysis. Venules connect the primary sinusoidal plexus of the hypothalamus (median eminence) with the secondary plexus in the anterior lobe of the hypophysis, forming the hypophysial-portal system. This system transports releasing factors from the hypothalamus to stimulate the secretion of hormones into the bloodstream by cells of the anterior hypophysis.

Endothelial cell-mediated regulation of blood flow

The general assumption that the endothelium is just an inert simple squamous epithelium lining blood vessels is no longer correct. In addition to enabling the passage of molecules and gases and retaining blood cells and large molecules, endothelial cells produce vasoactive substances that can induce contraction and relaxation of the smooth muscle vascular wall (Figure 12-13).

Figure 12-13 Endothelium

Nitric oxide, synthesized by endothelial cells from L-arginine upon stimulation by acetylcholine or other agents, activates guanylate cyclase and consequently cyclic guanosine monophosphate (cGMP) production, which induces relaxation of the smooth muscle cells of the vascular wall. Endothelin 1 is a very potent vasoconstrictor peptide produced by endothelial cells.

Prostacyclin, synthesized from arachidonic acid by the action of cyclooxygenase and prostacyclin synthase in endothelial cells, determines the relaxation of vascular smooth muscle cells by the action of cyclic adenosine monophosphate (cAMP). Synthetic prostacyclin is used to produce vasodilation in severe Raynaud’s phenomenon (pain and discoloration of the fingers and toes produced by vasospasm), ischemia, and in the treatment of pulmonary hypertension. Prostacyclin also prevents platelet adhesion and clumping leading to blood clotting.

The endothelium has a passive role in the transcapillary exchange of solvents and solutes by diffusion, filtration, and pinocytosis. The permeability of capillary endothelial cells is tissue-specific. Liver sinusoids are more permeable to albumin than are the capillaries of the renal glomerulus. In addition, there is a topographic permeability. The endothelial cells at the venous end are more permeable than those at the arterial end. Postcapillary venules have the greatest permeability to leukocytes.

Finally, recall the significance of endothelial cells in the process of cell homing and inflammation.

Clinical significance: Atherosclerosis

Atherosclerosis is the thickening and hardening of the walls of arteries caused by atherosclerotic plaques of lipids, cells, and connective tissue deposited in the tunica intima. Atherosclerosis is frequently seen in arteries sustaining high blood pressure, it does not affect veins and is the cause of myocardial infarction, stroke, and ischemic gangrene.

Atherosclerosis is now recognized as a chronic inflammatory disease, characterized by features of inflammation at all stages of its development (Figure 12-14). The atherosclerotic process is initiated when cholesterol-containing low-density lipoproteins (LDLs) accumulate in the intima as a consequence of endothelial cell dysfunction. A dysfunctional endothelium expresses vascular cell adhesion molecule-1 (VCAM-1) that enables monocytes to attach to the endothelial cell surface, cross the endothelium and penetrate the intima of the blood vessel. Monocytes then differentiate into macrophages expressing on their surface scavenger receptor-A (SR-A). SR-A uptakes a modified form of LDL (oxidized LDL) and the massive accumulation transforms macrophages into cholesterol-laden foam cells. Macrophage foam cells constitute the atheroma core of the atherosclerotic plaque.

The atheroma core continues to enlarge and smooth muscle cells of the tunica muscularis migrate to the intima forming a collagen-containing fibrous cap overlying the atheroma core. The endothelium covers the fibrous cap. The lipid core enlarges and triggers an inflammatory response attracting T cells that stimulate macrophage foam cells to produce metalloproteinases that, together with proinflammatory cytokines produced by T cells, weaken the fibrous cap making it susceptible to fracture that predisposes to thrombosis in the presence of procoagulant tissue factor. An enlarging thrombus will eventually obstruct or occlude the lumen of the affected blood vessel.

The major blood vessels involved are the abdominal aorta and the coronary and cerebral arteries. Coronary arteriosclerosis causes ischemic heart disease and, when the arterial lesions are complicated by thrombosis, myocardial infarction occurs. Atherothrombosis of the cerebral vessels is the major cause of brain infarct, so-called stroke, one of the most common causes of neurologic disease. Arteriosclerosis of the abdominal aorta leads to abdominal aortic aneurysm, a dilation that sometimes ruptures to produce massive fatal hemorrhage.

Atherosclerosis correlates with the serum levels of cholesterol or low-density lipoprotein (LDL). A genetic defect in lipoprotein metabolism (familial hypercholesterolemia) is associated with atherosclerosis and myocardial infarction before patients reach 20 years of age. We discussed in Chapter 2, Epithelial Glands, that familial hypercholesterolemia is caused by defects in the LDL receptor, resulting in increasing LDL circulating levels in blood. In contrast to LDL, high-density lipoprotein (HDL) transports cholesterol to the liver for excretion in the bile (see in the gallbladder section of Chapter 17, Digestive Glands).

Vasculogenesis and angiogenesis

After birth, angiogenesis contributes to organ growth. In the adult, most blood vessels remain stable and angiogenesis occurs in the endometrium and ovaries during the menstrual cycle, and in the placenta during pregnancy. Under pathologic conditions, angiogenesis is excessive during malignant (see Box 12-C), ocular (age-related macular degeneration), and inflammatory conditions.

An understanding of vasculogenesis and angiogenesis is relevant to developing therapeutic strategies to produce revascularization of ischemic tissues or inhibit angiogenesis in cancer, ocular, joint, or skin disorders.

The vascular system is formed by two processes (Figure 12-15):

Figure 12-14 Formation of an atherosclerotic plaque

Figure 12-15 Angiogenesis

Endothelial cells are involved in vasculogenesis and angiogenesis. Endothelial cells migrate, proliferate, and assemble into tubes to contain the blood. Periendothelial cells (smooth muscle cells, pericytes, and fibroblasts) are recruited to surround the newly formed endothelial tubes.

The following molecules are central to vascular morphogenesis: (1) Vascular endothelial cell factors (VEGFs), with binding affinity to two different receptors, VEGF-R1 and VEGF-R2, present on endothelial cells; (2) Tie2, a receptor tyrosine kinase that modulates a signaling cascade required for the induction or inhibition of endothelial cell proliferation. Angiopoietins 1 and 2 (Ang1 and Ang2) bind to the Tie2 receptor (for tyrosine kinase with immunoglobulin-like and EGF-like domains). Ang1 binding to Tie2 has a stabilizing effect on blood vessels (proangiogenic), whereas Ang2 has a destabilizing effect (anti-angiogenic).

The extracellular region of VEGF-R and Tie receptors is an immunoglobulin-like domain; the intracellular domain has tyrosine kinase activity. Upon ligand binding, the receptors dimerize and the intracellular domain autophosphorylates.

The Notch receptor is a third pathway (Figure 12-16). Notch receptor signaling facilitates endothelial cell survival by activating the expression of a VEGF-R that protects endothelial cells from apoptosis. Notch receptor Delta-like ligands (Dll1, Dll3 and Dll4) and Jagged (Jagged 1 and Jagged 2) play significant roles in normal and tumoral angiogenesis by regulating the actions of VEGF.

Figure 12-16 Tumor angiogenesis

Activation of Notch signaling is dependent on cell-cell interaction. It occurs when the extracellular domain of Notch receptor interacts with a ligand found on the surface of a nearby cell. Notch receptors participate in transcriptional regulation by a unique mechanism involving the cleavage of the Notch intracellular domain (NICD), which then translocates to the nucleus and regulates gene expression.

Clinical significance: Tumor angiogenesis and tumor-starving therapy

All the three signaling pathways, VEGF-R-VEGF, Tie-Ang, and Notch receptor-Dll/Jagged, contribute synergistically to the process of angiogenesis. Antiangiogenic drugs exert therapeutic effects by blocking certain specific receptors of the VEGF-VEGF-R pathway, but none can fully block all the components. Thus, angiogenesis signaling can continue through the other signaling pathways.

In Chapter 4, Connective Tissue, we discussed the molecular biology of tumor invasion. We briefly mentioned that tumors secrete angiogenic factors that increase the vascularization and nutrition of an invading tumor. These angiogenic factors are similar to those produced during normal wound healing. In addition, we indicated that newly formed blood vessels facilitate the dissemination of tumor cells to distant tissues (metastasis).

Given the belief that blocking blood supply starves tumors and the importance of VEGF and its receptor and receptor tyrosine kinase inhibitors (RTKIs) in angiogenesis, tumor antiangiogenic therapeutic approaches have been developed to provide cancer patients maximal survival time. Therapy with angiogenesis inhibitors reduce tumor growth but promote tumor invasiveness and metastasis (see Figure 12-16).

How can tumor invasiveness and metastasis be explained following VEGF-targeted therapy? A possible mechanism is tumor hypoxia. Following antiangiogenic tumor treatment, a lack of oxygen supply to the tumor selects for metastasis the less sensitive cells to treatment. These cells escape the hypoxic environment leading to increasing metastasis by expressing hypoxia-inducible factor-1 (HIF-1). HIF-1 is a survival factor of cancer cells by activating transcription of genes involved in angiogenesis. We discussed in Chapter 6, Blood and Hematopiesis, the role of hypoxia-inducible factor-1α in the production of erytropoietin, a regulator of erythropoiesis, under conditions of low oxygen tension.

The identification of biomarkers to monitor metastasis switch and resistance of cancer cells to antiangiogenic strategies could overcome the adverse effects of tumor-starving therapy.

Concept mapping

Cardiovascular System