What is the bundle of three blood vessels that connects an unborn baby with the placenta?

The Sympathetic Nervous System and Renal Vascular Reactivity

Within the kidney, the sympathetic nervous system modulates activity of the RAAS, sodium transport, and vascular function and thereby contributes to blood pressure through regulation of vascular tone and volume status.75 Development of the renal sympathetic nervous system and how this may be programmed during nephrogenesis, and modulated by the RAAS, is expertly reviewed by Kett and Denton.75 Renal denervation has been shown to abrogate development of adult hypertension and alter sodium transporter expression in the prenatal dexamethasone and uterine ischemia programming models, as well as the age-associated hypertension that develops in growth-restricted female rats.156,172,173 Consistent with the whole animal findings, within the kidney, an increase in baseline renal vascular resistance has been described in several programming models.174–176 For example, renal arterial responses to β-adrenergic stimulation and sensitivity to adenylyl cyclase were increased in 21-day-old growth-restricted offspring subjected to placental insufficiency.177 Although the renal expression of β2-adrenoreceptor mRNA was increased in these pups, there was also evidence of adaptations to the signal transduction pathway contributing to the β-adrenergic hyperresponsiveness.177 Intriguingly, these findings were much more marked in the right compared with the left kidney, an observation that remains unexplained but that is not without precedent: asymmetry of renal blood flow was found in 51% of a cohort of hypertensives without renovascular disease.177,178 In this study, the growth-restricted rats had low glomerular number, glomerular hyperfiltration, and hyperperfusion, and had significantly increased proteinuria compared with controls, suggesting alteration in glomerular pressures likely mediated by renal vasoreactivity. Interestingly, in a cohort of white and black U.S. subjects, the effect of birth weight on subsequent blood pressures was significantly modified by β-adrenergic receptor genotype, further underscoring a relationship between birth weight, sympathetic activity, and blood pressure.179

Vascular System

The vascular system or the circulatory system carries blood and lymph throughout the body. The blood vessels like arteries and veins carry blood throughout the body, transporting oxygen and nutrients to the pheripheral tissues and removing the wastes from target tissues. The lymph vessels filter and drain lymph from the body to maintain the fluid environment. The dysfunction of the vascular system therefore causes critical pathologies including cardiovascular diseases (e.g., hypertension, atherosclerosis, and restenosis), tumor angiogenesis, and cancer metastasis.

The endothelium lining the inner layers of blood vessels in the cardiovascular system experiences pulsatile flow-induced wall shear stress and transmural pressure, and pericytes and smooth muscle cells wrapping the outer walls of blood vessels contribute to the stabilization of the vascular system (Fig. 1A). Intercellular communication between these cells is regulated by signaling pathways such as through gap junctions that allow the exchange of metabolites, ions, and other essential molecules. Direct interaction between endothelial cells and smooth muscle cells faciliates the synchronization of their behaviors along the vascular wall.

The microengineered vascular system represents an undisputed advance in developing physiologically relevant vasculature models. The microfluidic device integrated with micropost structures allows for the investigation of microvessel formation, organization, and function under highly controlled conditions including biochemical gradients and flow-mediated dynamics. One representative approach is to replicate vasculogenic formation and angiogenic sprouting morphogenesis at the intraluminal side of the microvascular network (Fig. 1B). The extracellular matrix-mimicking hydrogels are being developed to provide more physiologically relevant 3D microenvironment to vascular endothelial cells, pericytes, and smooth muscle cells. Recent advances in 3D bioprinting technology allow high-precision construction of microarchitechture with hydrogel bioinks containing vascular cells and extracellular matrix components. This recapitulation of the complex microarchitechture of a human vascularized tissue combined with precisely controlled flow conditions with physiological context enables a perfusable capillary network within 3D extracelluar matrix and maintains the endothelial barrier function.

Despite progress in engineering vascular systems, reproduction of the key biophysical and biochemical features of the basement membrane and interstitial matrix in the microengineered vascular systems with the desired luminal structure and size requires more physiologically relevant biomaterials and advanced microfabrication approaches. Co-culture with stromal cells and immune cells in the developed vascular models is being studied with better maintenance of phenotypic cell stability and intercommunication. Modeling of complicated vascular functions including regulation of blood pressure, vasoactivity, hemostatic balance, permeability, and immunity and complex pathological conditions including thrombus formation and ischemia/reperfusion injury remains challenging.

Fetal Heart and Vascular System

The four-chamber view of the heart has been established as an important part of the routine fetal anatomic survey. However, as this view became incorporated into the routine survey, many examiners noted that outflow tract abnormalities were being missed. This occurs because many outflow tract abnormalities do not affect the appearance of the four-chamber view. The practice parameters adopted by the American Institute of Ultrasound in Medicine, American College of Radiology, and American College of Obstetricians and Gynecologists in 2013 suggested that there is a benefit in incorporating the right and left ventricular outflow tracts into the fetal survey to detect more cardiac anomalies.

Obtaining these views requires freehand sweeping of the transducer in a plane transverse and parallel to the four-chamber view of the heart. This can be difficult, and small deviations in transducer position will alter the displayed anatomy. TUI is a method of simultaneously displaying multiple sequential cardiac images with the ability to rotate the image in any plane desired. It can be thought of as being analogous to computed tomography imaging. TUI images can be displayed with either static or gated cardiac motion64 (spatiotemporal image correlation [STIC]) volume acquisitions. A major benefit of TUI is the ability to evaluate the heart either in real time (i.e., at the time of scanning) or offline at a later time, using the data acquired during scanning. DeVore and Polanko demonstrated that TUI decreases the time spent evaluating cardiac anatomy.65 Other techniques such as color Doppler, power Doppler, high-definition Doppler, B-flow, and various rendering techniques were used by Gindes and coworkers to assess 81 fetuses with cardiac anomalies and were found to make a major contribution in classifying cardiac anomalies from volume data.66 Turan and Yagel and their colleagues also reviewed the benefits of these various techniques in assessing cardiac anomalies.67,68

Gonçalves and coauthors described a method for examining the fetal heart using 4D US and STIC, a method allowing acquisition of a fetal heart volume and its visualization as a 4D cine sequence.69 Only one satisfactory volume data set needs to be obtained. Acquisition is performed with an automated slow sweep, and frames are sequentially acquired at a rapid rate. This method also is valuable for 3D surface rendering of structures such as cardiac valves. STIC allows the entire volume of the heart to be evaluated; it is useful for diagnosis and for teaching (Fig. 20.10). The STIC technology allows for the heart to be rotated using the cursor dot in any plane. For example, in transposition of the great vessels (Fig. 20.11), the bifurcation of the pulmonary artery can be seen in one plane and its relationship to the left ventricle (i.e., abnormal outlet) can be seen in another plane.

Summary

The vascular system is a critical component of organismal development. A well-patterned and physiologically responsive circu­latory system ensures proper nutrient and oxygen delivery for the growth and development of the embryo. It requires de novo formation of major vessels (vasculogenesis), in addition to rapid, organized expansion of vascular beds from preexisting vessels (angiogenesis). We have reviewed the overarching principles governing the formation of the vascular system within the embryo and the main signaling cascades responsible for its organization. Foremost to the importance of a functioning vascular system is the specification of endothelial cells into arterial, vein, and lymphatic cell subsets and the establishment of their respective circulatory systems. In the adult, the expansion of the vasculature addresses the needs of growing tissues and, when necessary, promotes repair and regeneration. Interestingly, similar signaling mechanisms are echoed throughout each vascular process. The Notch pathway, in addition to VEGF and hypoxia, all play integral roles in vascular development and disease. The intersection of these pathways, combined with the increased ability to detect human gene and genomic variants, will continue to reveal the complex and interwoven system of signaling cascades in normal vascular formation and function. In addition to forming a circulatory system on the organismal level, the regulation and formation of the vasculature are also responsible for proper formation and maintenance of specific organs. Thus we have also highlighted the role of the vascular system in organogenesis. Similar principles hold for angiogenesis in the context of tumor formation. As antiangiogenic agents continue to be created and tested as cancer therapies, new opportunities will arise for therapeutic exploration in vascular disease. We are beginning to realize the benefits of this new information with novel treatments for ROP.

Structure and Function of the Cutaneous Lymphatic Vascular System

Lymphatic vessels were first described in the seventeenth century by Gaspare Aselli as “lacteae venae” (milky veins). The cutaneous lymphatic system develops in parallel with the blood vascular system through a process termed lymphangiogenesis, and lymphatic vessels are not present in avascular structures such as epidermis, hair, and nails22. The lymphatic system is composed of a vascular network of thin-walled capillaries that drain protein-rich lymph from the extracellular space and play a crucial role in the maintenance of normal tissue pressure. Lymphatic vessels also play an important role in mediating the trafficking of immune cells from the skin to the regional lymph nodes, and in the metastatic spread of cutaneous malignancies23.

Lymphatic capillaries are lined by a continuous single-cell layer of overlapping endothelial cells and lack a continuous basement membrane. In initial lymphatics, overlapping flaps at the borders of oak leaf-shaped endothelial cells lack junctions at their tips but are anchored on the sides by discontinuous button-like junctions; the latter differ from the conventional, continuous, zipper-like junctions found in larger collecting lymphatics and blood vessels24. Lymph returns to the venous circulation via larger lymphatic collecting vessels, which contain a muscular and adventitial layer as well as numerous valves, and the thoracic duct and right lymphatic duct that are connected, via lymphovenous valves, to the subclavian veins.

The lymphatic vessels of the skin form two horizontal plexuses. The superficial plexus collects lymph from lymphatic capillaries and is located in close vicinity to the superficial cutaneous arterial plexus. Vertical lymphatic vessels connect the superficial plexus with the larger collecting vessels in the lower dermis and upper subcutis, whereas few lymphatics are found within the subcutis (seeFig. 102.1). The deep lymphatic vessels are located below the deep arterial system and contain valves to ensure unidirectional fluid transport.

The structure of the cutaneous lymphatics is dependent on the structure of the skin at a particular site and can vary significantly. Lymphatic vessels have a regular, uniform shape where the skin is firm and thick, whereas the shapes are more variable in regions where the skin is thin and loose. Certain areas, such as the fingers, the palms and soles, the scrotum and the foreskin, appear to have a more abundant lymphatic network.

Lymphatic capillaries respond to increased tissue fluid content by widening their lumina (Fig. 102.12), an action mediated by anchoring filaments that connect the lymphatic endothelial cells with the surrounding interstitium. In normal skin, the majority of lymphatic vessels are collapsed. Whereas elevation of the interstitial pressure up to +2 mmHg results in both distention of lymphatic vessels and increased lymph flow, higher interstitial fluid pressure results in edema formation. The detection of enlarged lymphatics in the skin, however, does not allow predictions about their function because overextended lymphatics can be dysfunctional, as in some types of lymphedema25. It is thought that increased fluid load in the tissue mediates activation of lymphatic vessel drainage function via mechanosensors in lymphatic endothelium26.

Congenital Hepatic Vascular Shunts

The vascular system begins to form during the third week of gestation as a network of interlacing blood spaces in primitive mesenchyme. The system gradually develops by processes of vascular coalescence and cellular differentiation that culminates in separate arterial and venous conduits. Congenital intrahepatic shunts are very rare anomalies characterized by abnormal communication between the hepatic arterial system, portal veins, hepatic veins, or systemic veins as a result of disordered embryologic development around the fifth gestational week. Normal development of the hepatic vascular system commences with anastomosis of the paired vitelline veins, as they enter the septum transversum and intersperse with rapidly proliferating hepatocytes. The left vitelline vein involutes, and the blood is redistributed to the right vitelline vein, which enlarges and forms the terminal inferior vena cava, hepatic veins, and portal vein.

The paired umbilical veins bring oxygenated blood to the embryo and course on either side of the liver. When they contact the hepatic sinusoids, the right umbilical vein and portions of the left umbilical vein become obliterated; the persistent left umbilical vein carries blood from the placenta to the fetus. A large channel, the ductus venosus, connects the left umbilical vein to the inferior vena cava to allow oxygenated blood to bypass sinusoid circulation (Gallego et al, 2004). Any deviation from the normal vascular system's embryologic development can lead to abnormal fistulae and shunting (Fig. 104.3).

Abstract

The vascular system, which is highly dynamic, has multiple functions including transport (oxygen and nutrients), volume and blood pressure control (vasoconstriction/dilation), immune function (leukocyte–vessel interactions), and mechanical function (erectile tissues). Vessels comprise three main layers: an inner endothelial layer, a middle vascular media, and an outer adventitia. Of the many cell types that make up the vascular wall, vascular smooth muscle cells are particularly important since they have a high degree of phenotypic variability. In addition to changes in contractility, vascular function is influenced by structural characteristics. Vasoactive agents such as angiotensin II regulate vascular function and structure, and in pathological conditions contribute to vascular dysfunction and vascular remodeling. Other factors such as endothelial progenitor cells (EPCs) and microparticles may also impact on vascular function in health and disease. This article discusses mechanisms regulating vascular function and structure and highlights the importance of the renin-angiotensin system in health and disease. New concepts relating to circulating EPCs and microparticles in vascular regulation are introduced.

2 The Plant Vascular System

The vascular system of extant seed plants is a network of continuous files of cells organized in strands (or bundles) that extend through each organ and throughout the entire plant, functionally connecting every part of the shoot with the root system (Esau, 1965; Fig. 8.1A). At maturity, vascular strands typically represent the organization of two vascular tissues, the phloem and the xylem. The phloem represents the route for translocation of dissolved carbohydrates, which are transported from tissues that are net producers of photoassimilates to tissues that are net users, while the xylem is the main conduit for transport of water and minerals from the root to the sites of evapo-transpiration in the shoot. Furthermore, phloem and xylem are responsible for the distribution of a variety of regulatory molecules involved in plant development, response to the environment, and defense against pathogens (Cambridge and Morris, 1996; Citovsky and Zambryski, 2000; Hirose et al., 2008; Jiang and Hartung, 2008; Lough and Lucas, 2006; Oparka and Cruz, 2000; van Bel et al., 2002). Finally, both vascular tissues typically comprise a number of specialized cell types, including conducting elements, and cells that fulfill nourishing and supporting functions.

4.18 Is the Endothelium Seamless?

The vascular system is apparently seamless. Many clinical studies have shown that advanced endothelium impairment in any segment predicts likewise impairment in other segments. However, there is some doubt that endothelium impairment—all factors equal—begins uniformly at the same time in all parts of the vascular system. If that is the case, then the schemata for the age-related atherosclerosis timeline is misleading because it assumes that all parts of the vascular system begin to develop plaque deposits at about the same time. There may be good reason to think that the endothelium is not functionally seamless, and if that is so, it is not good news.

A report published in European Urology concerned the results of a study comparing “penile and systemic endothelial function in men with and without erectile dysfunction.” The participants were divided into two groups, those with ED and those without ED, according to their International Index of Erectile Function (IIEF) ED domain scores. Blood flow measurements, penile endothelial function, and forearm endothelial function were assessed in all participants using veno-occlusive plethysmography (see Chapter 10).

General characteristics of the two groups of participants were comparable except for age. Forearm blood flow was similar in the two groups, but the penile blood flow was significantly lower in men with ED compared with that in the men without ED. Penile vascular resistance was higher in the ED group compared with the control group. The indices of forearm endothelial function were comparable in both groups. However, indices of penile endothelial function were significantly higher in the control group compared with those of the ED group.

This is the first study that shows impaired penile endothelial function “without the presence of a significant peripheral endothelial dysfunction” (my italics).33 In other words, endothelial dysfunction in the penis blood vessels preceded endothelial dysfunction in other regions of the vasculature: The penis may be at risk of atherosclerosis even before other parts of the body are targeted.

6.1 Microscopic Anatomy

The vascular system is subdivided into arterial, capillary, venous, and lymphatic segments. The arteries are classified into three types: elastic arteries, muscular arteries, and arterioles. The venous vessels are termed venules and veins. Interposed between the arterial and venous segments are the capillary beds. Some authors prefer to further define a vascular segment, termed the microcirculation, which includes arterioles, capillaries, and venules and serves as the major area of exchange between the circulating blood and the peripheral tissues. The lymphatic vasculature includes lymph capillaries and lymphatic vessels.

The overall design of the blood and lymphatic vessels is similar except that lumenal diameter, wall thickness, and the presence of other anatomic features such as valves vary between the different segments of the system. The lumenal surface of all vessels is lined by longitudinally aligned endothelial cells lying over a basal lamina. Vascular walls are divided into three layers: intima, media, and adventitia. However, some or all of the layers may be absent or thinned in some segments of the vascular system, depending on the intravascular pressures. The large elastic arteries, such as the aorta, have an intimal layer composed of endothelium and subendothelial connective tissue; and a very thick medial layer composed of concentrically arranged layers of smooth muscle cells alternating with fenestrated elastic laminae and small amounts of ground substance. The media is demarcated by the internal and external elastic laminae. The outermost layer, the adventitia, is composed of collagen, elastic fibers, and connective tissue cells with penetrating blood vessels, termed the vasa vasorum, that supply nutrition to the adventitia and the outer half of the media. In muscular arteries and arterioles, the media is largely composed of smooth muscle cells arranged in a circumferential pattern (Figure 46.18).

Arterioles are the smallest arterial channels, and are generally recognized as vessels of less than 100 μm in diameter surrounded by one to three layers of smooth muscle cells.

Capillaries are 5–10 μm in diameter and have an endothelium of one of three types: continuous, fenestrated (as in the endocrine glands), and porous (as in renal glomeruli). The endothelium rests on an external lamina surrounded by pericytes. Lesions in the endothelium may require electron microscopy to be visualized.

Veins have thin walls in relation to their lumenal size when compared with arteries, where blood pressures are higher (Figure 46.19). The adventitia is the thickest layer. Valves are present to prevent retrograde blood flow away from the heart.

Lymphatic capillaries lack basal laminae. Large lymphatic vessels appear similar to veins, with large lumina, thin walls, and intimal valves, but will contain lymph, evident as eosinophilic serum protein deposits devoid of erythrocytes, rather than blood as in veins.