Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

BLOOD VESSELS, LYMPHATICS, AND ENDOTHELIAL CELLS
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those of a neuronal growth cone. The column of stalk cells behind it, meanwhile,
becomes hollowed out to form a lumen.
The endothelial tip cells that pioneer the growth of normal capillaries not only
look like neuronal growth cones, but also respond similarly to signals in the environment.
In fact, many of the same guidance molecules are involved, including
the netrins, slits, and ephrins mentioned in our account of neural development
in the previous chapter. The corresponding receptors are expressed in the tip cells
and guide the vascular sprouts along specific pathways in the embryo, often in
parallel with nerves. Perhaps the most important of the guidance molecules for
endothelial cells, however, is one that is chiefly dedicated to the control of vascular
development: vascular endothelial growth factor, or VEGF.
Tissues Requiring a Blood Supply Release VEGF
Almost every cell, in almost every tissue of a vertebrate, is located within
50–100 μm of a blood capillary. What mechanism ensures that the system of blood
vessels branches 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
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 22–25). 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.
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 vascular endothelial growth factor (VEGF). 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 level of a transcription factor
called hypoxia-inducible factor 1α (HIF1α). HIF1α stimulates transcription
of Vegf (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, stimulating them to proliferate, to produce proteases
to help them digest their way through the basal lamina of the parent capillary or
venule, and to form sprouts. The tip cells of the sprouts detect the VEGF gradient
and move toward its source. As the new vessels form, bringing blood to the tissue,
the oxygen concentration rises. The HIF1α activity then declines, VEGF production
is shut off, and angiogenesis comes to a halt (Figure 22–26).
control
60 hours after wounding
100 µm 100 µm
Figure 22–25 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 the resin set;
this reveals the shape of the lumen, as
opposed to the shape of the cells. Sixty
hours after wounding, many new capillaries
have begun to sprout toward the site of
injury, which is just above the top of the
picture. Their oriented outgrowth reflects
a chemotactic response of the endothelial
cells to an angiogenic factor released at the
wound. (Courtesy of Peter C. Burger.)