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Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th edition. New York: Garland Science; 2002.

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Molecular Biology of the Cell. 4th edition.

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Blood Vessels and Endothelial Cells

From the tissues that derive from the embryonic ectoderm and endoderm, we turn now to those derived from mesoderm. This middle layer of cells, sandwiched between ectoderm and endoderm, grows and diversifies to provide a wide range of supportive functions. It gives rise to the body's connective tissues, blood cells, and blood vessels, as well as muscle, kidney, and many other structures and cell types. We begin with blood vessels.

Almost all tissues depend on a blood supply, and the blood supply depends on endothelial cells, which form the linings of the blood vessels. Endothelial cells have a remarkable capacity to adjust their number and arrangement to suit local requirements. They create an adaptable life-support system, extending by cell migration into almost every region of the body. If it were not for endothelial cells extending and remodeling the network of blood vessels, tissue growth and repair would be impossible. Cancerous tissue is as dependent on a blood supply as is normal tissue, and this has led to a surge of interest in endothelial cell biology. It is hoped that by blocking the formation of new blood vessels through drugs that act on endothelial cells, it may be possible to block the growth of tumors (discussed in Chapter 23).

Endothelial Cells Line All Blood Vessels

The largest blood vessels are arteries and veins, which have a thick, tough wall of connective tissue and and many layers of smooth muscle cells (Figure 22-22). The wall is lined by an exceedingly thin single sheet of endothelial cells, the endothelium, separated from the surrounding outer layers by a basal lamina. The amounts of connective tissue and smooth muscle in the vessel wall vary according to the vessel's diameter and function, but the endothelial lining is always present. In the finest branches of the vascular tree—the capillaries and sinusoids—the walls consist of nothing but endothelial cells and a basal lamina (Figure 22-23), together with a few scattered—but functionally important—pericytes. These are cells of the connective-tissue family, related to vascular smooth muscle cells, that wrap themselves round the small vessels (Figure 22-24).

Figure 22-22. Diagram of a small artery in cross section.

Figure 22-22

Diagram of a small artery in cross section. The endothelial cells, although inconspicuous, are the fundamental component. Compare with the capillary in Figure 22-23.

Figure 22-23. Capillaries.

Figure 22-23

Capillaries. (A) Electron micrograph of a cross section of a small capillary in the pancreas. The wall is formed by a single endothelial cell surrounded by a basal lamina. Note the small “transcytotic” vesicles, which according to one (more...)

Figure 22-24. Pericytes.

Figure 22-24

Pericytes. The scanning electron micrograph shows pericytes wrapping their processes around a small blood vessel (a post-capillary venule) in the mammary gland of a cat. Pericytes are present also around capillaries, but much more sparsely distributed (more...)

Thus, endothelial cells line the entire vascular system, from the heart to the smallest capillary, and control the passage of materials—and the transit of white blood cells—into and out of the bloodstream. A study of the embryo reveals, moreover, that arteries and veins develop from small vessels constructed solely of endothelial cells and a basal lamina: pericytes, connective tissue and smooth muscle are added later where required, under the influence of signals from the endothelial cells. The recruitment of pericytes in particular depends on PDGF-B secreted by the endothelial cells, and in mutants lacking this signal protein or its receptor, pericytes in many regions are missing. As a result, the embryonic blood vessels develop microaneurysms—microscopic pathological dilatations—that eventually rupture, as well as other abnormalities, reflecting the importance of signals exchanged in both directions between the pericytes and the endothelial cells.

Once a vessel has matured, signals from the endothelial cells to the surrounding connective tissue and smooth muscle continue to play a crucial part in regulating the vessel's function and structure. For example, the endothelial cells have mechanoreceptors that allow them to sense the shear stress due to flow of blood over their surface; by signaling this information to the surrounding cells, they enable the blood vessel to adapt its diameter and wall thickness to suit the blood flow. Endothelial cells also mediate rapid responses to neural signals for blood vessel dilation, by releasing the gas NO to make smooth muscle relax in the vessel wall, as discussed in Chapter 15.

New Endothelial Cells Are Generated by Simple Duplication of Existing Endothelial Cells

Throughout the vascular system of the adult body, endothelial cells retain a capacity for cell division and movement. If, for example, a part of the wall of the aorta is damaged and denuded of endothelial cells, neighboring endothelial cells proliferate and migrate in to cover the exposed surface.

The proliferation of endothelial cells can be demonstrated by using 3H-thymidine to label cells synthesizing DNA. In most adult tissues, endothelial cells turn over very slowly, with a cell lifetime ranging, for a mouse, from a couple of months (in liver and lung) to years (in brain and muscle). But endothelial cells not only repair and renew the lining of established blood vessels, they also create new blood vessels. They must do this in embryonic tissues to keep pace with growth, in normal adult tissues to support recurrent cycles of remodeling and reconstruction (as, for example, in the lining of the uterus during the menstrual cycle), and in damaged adult tissues to support repair. In such circumstances, they can be roused to proliferate with a doubling time of just a few days. There is some evidence that, where there is a call for rapid blood-vessel growth, the local population of endothelial cells may also increase by recruitment from the blood stream, which has been reported to contain small numbers of endothelial precursor cells derived from the bone marrow.

New Capillaries Form by Sprouting

New vessels in the adult originate as capillaries, which sprout from existing small vessels. This process of angiogenesis occurs in response to specific signals and can be conveniently observed in naturally transparent structures, such as the cornea of the eye. Irritants applied to the cornea induce the growth of new blood vessels from the rim of tissue surrounding the cornea, which has a rich blood supply, in toward the center of the cornea, which normally has none. Thus, the cornea becomes vascularized through an invasion of endothelial cells into the tough collagen-packed corneal tissue.

Observations such as these reveal that endothelial cells that are to form a new capillary grow out from the side of an existing capillary or small venule by extending long pseudopodia, pioneering the formation of a capillary sprout that hollows out to form a tube (Figure 22-25). This process continues until the sprout encounters another capillary, with which it connects, allowing blood to circulate. Endothelial cells on the arterial and venous sides of the developing network of vessels differ in their surface properties, in the embryo at least: the plasma membranes of the arterial cells contain the transmembrane protein ephrin-B2 (see Chapter 15), while the membranes of the venous cells contain the corresponding receptor protein, Eph-B4, which is a receptor tyrosine kinase (discussed in Chapter 15). These molecules mediate a signal delivered at sites of cell-cell contact, and they are essential for the development of a properly organized network of vessels. One suggestion is that they somehow define the rules for joining one piece of growing capillary tube to another.

Figure 22-25. Angiogenesis.

Figure 22-25

Angiogenesis. A new blood capillary forms by the sprouting of an endothelial cell from the wall of an existing small vessel. This diagram is based on observations of cells in the transparent tail of a living tadpole. (After C.C. Speidel, Am. J. Anat. (more...)

Experiments in culture show that endothelial cells in a medium containing suitable growth factors will spontaneously form capillary tubes, even if they are isolated from all other types of cells (Figure 22-26). The capillary tubes that develop do not contain blood, and nothing travels through them, indicating that blood flow and pressure are not required for the initiation of a new capillary network.

Figure 22-26. Capillary formation in vitro.

Figure 22-26

Capillary formation in vitro. Endothelial cells in culture spontaneously develop internal vacuoles that appear to join up from cell to cell, giving rise to a network of capillary tubes. These photographs show successive stages in the process. The arrow (more...)

Angiogenesis Is Controlled by Factors Released by the Surrounding Tissues

Almost every cell, in almost every tissue of a vertebrate, is located within 50–100 μm of a capillary. What mechanism ensures that the system of blood vessels ramifies into every nook and cranny? How is it adjusted so perfectly to the local needs of the tissues, not only during normal development but also in all sorts of pathological circumstances? Wounding, for example, induces a burst of capillary growth in the neighborhood of the damage, to satisfy the high metabolic requirements of the repair process (Figure 22-27). Local irritants and infections also cause a proliferation of new capillaries, most of which regress and disappear when the inflammation subsides. Less benignly, a small sample of tumor tissue implanted in the cornea, which normally lacks blood vessels, causes blood vessels to grow quickly toward the implant from the vascular margin of the cornea; the growth rate of the tumor increases abruptly as soon as the vessels reach it.

Figure 22-27. New capillary formation in response to wounding.

Figure 22-27

New capillary formation in response to wounding. Scanning electron micrographs of casts of the system of blood vessels surrounding the margin of the cornea show the reaction to wounding. The casts are made by injecting a resin into the vessels and letting (more...)

In all these cases, the invading endothelial cells respond to signals produced by the tissue that they invade. The signals are complex, but a key part is played by a protein known as vascular endothelial growth factor (VEGF), a distant relative of platelet-derived growth factor (PDGF). The regulation of blood vessel growth to match the needs of the tissue depends on the control of VEGF production, through changes in the stability of its mRNA and in its rate of transcription. The latter control is relatively well understood. A shortage of oxygen, in practically any type of cell, causes an increase in the intracellular concentration of the active form of a gene regulatory protein called hypoxia-inducible factor 1 (HIF-1). HIF stimulates transcription of the VEGF gene (and of other genes whose products are needed when oxygen is in short supply). The VEGF protein is secreted, diffuses through the tissue, and acts on nearby endothelial cells.

The response of the endothelial cells includes at least four components. First, the cells produce proteases to digest their way through the basal lamina of the parent capillary or venule. Second, the endothelial cells migrate toward the source of the signal. Third, the cells proliferate. Fourth, the cells form tubes and differentiate. VEGF acts on endothelial cells selectively to stimulate this entire set of effects. (Other growth factors, including some members of the fibroblast growth factor family, can also stimulate angiogenesis, but they influence other cell types besides endothelial cells.)

As the new vessels form, bringing blood to the tissue, the oxygen concentration rises, HIF-1 activity declines, VEGF production is shut off, and angiogenesis comes to a halt (Figure 22-28). As in all signaling systems, it is as important to switch the signal off correctly as to switch it on. In normal well-oxygenated tissue, the concentration of HIF-1 is kept low by continual degradation of the HIF-1 protein. This degradation depends on ubiquitylation of HIF-1—a process that requires the product of another gene, which is defective in a rare disorder called von Hippel-Lindau (VHL) syndrome. People with this condition are born with only one functional copy of the VHL gene; mutations occurring at random in the body then give rise to cells in which both gene copies are defective. These cells contain large quantities of HIF-1 regardless of oxygen availability, triggering the continual overproduction of VEGF. The result is development of hemangioblastomas, tumors that contain dense masses of blood vessels. The mutant cells that produce the VEGF are apparently themselves encouraged to proliferate by the over-rich nourishment provided by the excess blood vessels, creating a vicious cycle that promotes tumor growth. Loss of the VHL gene product also gives rise to other tumors as well as hemangioblastomas, by mechanisms that may be independent of effects on angiogenesis.

Figure 22-28. The regulatory mechanism controlling blood vessel growth according to a tissue's need for oxygen.

Figure 22-28

The regulatory mechanism controlling blood vessel growth according to a tissue's need for oxygen. Lack of oxygen triggers the secretion of VEGF, which stimulates angiogenesis.

Summary

Endothelial cells form a single cell layer that lines all blood vessels and regulates exchanges between the bloodstream and the surrounding tissues. Signals from endothelial cells organize the growth and development of connective tissue cells that form the surrounding layers of the blood-vessel wall. New blood vessels can develop from the walls of existing small vessels by the outgrowth of endothelial cells, which have the capacity to form hollow capillary tubes even when isolated in culture. Endothelial cells of developing arteries and veins express different cell-surface proteins, which may control the way in which they link up to create a capillary bed.

A homeostatic mechanism ensures that blood vessels permeate every region of the body. Cells that are short of oxygen increase their concentration of hypoxia-inducible factor 1 (HIF-1), which stimulates the production of vascular endothelial growth factor (VEGF). VEGF acts on endothelial cells, causing them to proliferate and invade the hypoxic tissue to supply it with new blood vessels.

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By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

Copyright © 2002, Bruce Alberts, Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, and Peter Walter; Copyright © 1983, 1989, 1994, Bruce Alberts, Dennis Bray, Julian Lewis, Martin Raff, Keith Roberts, and James D. Watson .
Bookshelf ID: NBK26848

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