The
Microcirculation And Lymphatic System, And Diapedesis
The microcirculation
comprises the smallest arterioles, and the exchange vessels,
including the capillaries and the postcapillary venules. The
transfer of gases, water, nutrients, waste materials and other substances between
the blood and body tissues carried out by the exchange vessels is the ultimate
function of the cardiovascular system.
Blood enters the microcirculation via small arterioles, the walls of
which contain smooth muscle cells. These vessels are densely innervated by the
sympathetic system, particularly in the splanchnic and cutaneous vascular beds.
Sympathetically mediated constriction of each small arteriole reduces the blood
flow to many capillaries.
In the vast majority of tissues, the smallest or terminal arterioles
divide to give rise to sets of capillaries (Figure 20a, left). The terminal
arteriole itself acts as a functional precapillary sphincter for its entire cluster of capillaries. Terminal
arterioles are not innervated, and their tone is controlled by local metabolic
factors (see Chapter 23). Under basal conditions, terminal arterioles constrict
and relax periodically. This vasomotion causes the flow of blood through
the cluster of capillaries to fluctuate.
In a few tissues, however (e.g. mesentery), capillaries branch from
thoroughfare vessels which run from small arterioles to venules (Figure 20a,
right). The proximal (arteriolar) end of such a vessel is termed a metarteriole,
and it is wrapped intermittently in smooth muscle cells. The capillaries have a
ring of smooth muscle called a precapillary sphincter at their origin,
but thereafter lack smooth muscle cells. Constriction of the precapillary
sphincter controls the flow of blood through that capillary.
The capillaries join to form postcapillary venules, which also lack
smooth muscle cells. These merge to form venules, which contain smooth muscle
cells and are sympathetically innervated.
Water, gases and solutes (e.g. electrolytes, glucose, proteins) cross the
walls of exchange vessels mainly by diffusion, a passive process by
which substances move down their concentration gradients. O2 and CO2
can diffuse through the lipid bilayers of the endothelial cells. These and
other lipophilic substances (e.g. general anaesthetics) therefore cross
the capillary wall very rapidly. However, the lipid bilayer is impermeable to
electrolytes and small hydrophilic (lipid-insoluble) molecules such as
glucose, which therefore cross the walls of continuous capillaries
(Figure 20b, bottom) 1000– 10 000 times more slowly than does O2.
Hydrophilic molecules cross the capillary wall mainly by diffusing between the
endothelial cells. This process is slowed by tight junctions between the
endothelial cells which impede diffusion through the intercellular clefts.
Diffusion is also retarded by the glycocalyx, a dense net- work of
fibrous macromolecules coating the luminal side of the endothelium. This
tortuous diffusion pathway (the small pore system) acts as a sieve which
admits molecules of molecular weight (MW) less than 10 000.
Even large proteins (e.g. albumin, MW 69 000) can cross the capillary
wall, albeit very slowly. This suggests that the capillary wall also contains a
small number of large pores, although these have never been directly
visualized. It has been proposed that large pores exist transiently when
membrane invaginations on either side of the endothelial cell fuse, temporarily
creating a channel through which large molecules diffuse.
The endothelial cells of fenestrated capillaries (found in
kidneys, intestines and joints) contain pores called fenestrae (Figure
20b, upper right) which render them ∼10
times more permeable than continuous capillaries to small hydrophilic
molecules, which can move through the
fenestrae. Sinusoidal or discontinuous capillaries (liver, bone
marrow, spleen) are very highly permeable, because they have wide spaces
between adjacent endothelial cells through which proteins and even erythrocytes
can pass (Figure 20b, upper left).
The composition of the extracellular fluid in the brain must be kept
extremely constant in order to allow stable neuronal function. This is made
possible by the existence of the blood–brain barrier (BBB), which
tightly controls the movement of ions and solutes across the walls of the
continuous capillaries within the brain and the choroid plexus. The BBB has two
important features. First, the junctions between the endothelial cells of
cerebral capillaries are extremely tight (resembling the zonae occludens of
epithelia), preventing any significant movement of hydrophilic solutes. Second,
specialized membrane transporters exist in cerebral endothelial cells which
allow the controlled movement of inorganic ions, glucose, amino acids and other
substances across the capillary wall. Thus, the relatively uncontrolled
diffusion of solutes present in other vascular beds is replaced in the brain by
a number of specific transport processes. This can present a therapeutic
problem, as most drugs are excluded from the brain (e.g. many antibiotics).
The BBB is interrupted in the circumventricular organs, areas of
the brain that need to be influenced by blood-borne factors, or to release
substances into the blood. These include the pituitary and pineal glands,
the median eminence, the area postrema and the choroid plexus.
The BBB can break down with large elevations of blood pressure, osmolarity or PCO2,
and in infected areas of the brain.
Diapedesis
In order to cause local inflammation in infected or damaged tissue,
leucocytes must leave the blood by migrating across the endothelium of nearby
venules, a process termed diapedesis (Figure 20c). Inflammatory mediators
released at the site of infection induce venular endothelial cells to express
E- and P-selectins and other adhesion molecules on their luminal surfaces.
Leucocytes express complementary surface adhesion molecules such as VLA4
and P-selectin glycoprotein ligand 1, and many leucocytes are therefore
captured as they flow by, at first rolling along the endothelial surface and
then stopping as their interaction with the endothelium and exposure to locally
released cytokines causes the expression and activation of additional adhesion
molecules on both types of cells (e.g.VCAM1 on
endothelial cells; β2 integrins on leucocytes). The leucocytes flatten and send out protrusions allowing
them to creep over the endothelium, seeking ‘permissive’ sites at which they
can enter the tissue by squeezing themselves through the junctions between adjacent
endothelial cells (paracellular transendothelial migration). Endothelial
cells aid this process by down-regulating the function of the junctional
plasmalemmal protein VE-cadherin which normally acts to hold the adjacent cells
close together at the junctions, and by transiently increasing the expression
of junctional adhesion molecules such as PECAM and JAM-A, which the leucocytes
use to pull themselves through. Alternatively, leucocytes are able to undergo transcellular
transendothelial migration, a process by which they tunnel directly through
rather than between endothelial cells to reach the interstitium. Following
endothelial transmigration, leucocytes are able to propel themselves through
weak spots in the layer of basement membrane and pericytes, gaining access to
the tissue.
The lymphatic system
Approximately 8 L of fluid containing solutes and plasma proteins is
filtered from the microcirculation into the tissue spaces each day. This
returns to the blood via the lymphatic system. Most body tissues contain lymphatic capillaries
(Figure 20a). These are blind- ended bulbous tubes 15–75 µm in diameter, with
walls formed of a monolayer of endothelial cells. Interstitial fluid, plasma
proteins and bacteria can easily
enter the lymphatic capillaries via the gaps between these cells, the
arrangement of which then prevents these substances from escaping. These
vessels merge to form collecting lymphatics, the walls of which contain
smooth muscle cells and one-way valves (as do the larger lymphatic vessels).
The sections between these valves constrict strongly, forcing the lymph towards
the blood. Lymph is also propelled by compression of the vessels by muscular
contraction, body movement and tissue compression. Lymph then enters the larger
afferent lymphatics, which flow into the lymph nodes. Here,
foreign particles and bacteria are scavenged by phagocytes, and can initiate the
production of activated lymphocytes. These enter the lymph for transport into
the circulation, where they mount an immune response. Much of the lymph returns
to the blood via capillary absorption in the lymph nodes. The rest enters efferent
lymphatics, most of which eventually merge into the thoracic duct.
This duct empties into the left subclavian vein in the neck. Lymphatics from
parts of the thorax, the right arm and the right sides of the head and neck
merge forming the right lymph duct, which enters the right subclavian
vein. The lymphatic system is also important in the absorption of lipids from
the intestines. The lacteal lymphatics are responsible for transporting
about 60% of digested fat into the venous blood.
