Microcirculation and Lymphatic Vessels (Chapter 22)

Objectives:

• Describe the regulation of regional blood flow by the arterioles
• Describe the physical and chemical factors affecting the vessels
• Explain the roles of diffusion, filtration and pinocytosis in transcapillary exchange
• Describe the balance between hydrostatic and osmotic forces under normal and abnormal conditions
• Describe the lymphatic circulation

The objective of the circulatory system is to deliver nutrients, O2 and fluid to the tissues and remove CO2 and other waste products. With proper control the circulation will deliver blood flow in an amount that matches tissue needs, at a pressure that maintains appropriate fluid balance to each tissue bed.

• Structure and Components of the Microcirculation

Blood flowing from the major arteries traverses progressively smaller arteries before entering the microcirculation (Fig. 1). As diagrammed above, blood passes through arterioles and then either into capillaries or into metarterioles and then into capillaries. Some blood passes through metarterioles into venules without traversing capillaries. This by-pass function has functional importance in the skin. However, the functionally important circuit for most vascular beds is from arterioles to capillaries to venules.

Arterioles, the vessels that give rise to capillaries, have diameters of 50 - 100 μm, and possess considerable smooth muscle. Contraction or relaxation of this smooth muscle alters the diameter of the arterioles, thus controlling pressure in the capillaries as well as the blood flow through them. Most arterioles have dense innervation by the sympathetic nervous system. Both neural and local factors may control arteriolar diameter in different vascular beds.

Metarterioles are intermediate in size between arterioles and capillaries. The wall of metarterioles contains modest amounts of vascular smooth muscle. Metarterioles may deliver blood to capillaries or by-pass the capillaries and deliver blood directly to the venules.

Capillaries have small diameters as small as 5 μm. Therefore, red blood cells, which have a diameter of 7 μm, are deformed as they squeeze through them. Capillary walls consist only of endothelial cells. Capillaries are only 0.5 -1.0 mm long, and since blood flows through them at the rate of 1 mm/sec, blood traverses the capillary in about one second. A ring of smooth muscle, the precapillary sphincter, surrounds the initial segment of many capillaries. Opening and closing of this sphincter allows or prevents blood from entering that capillary.

The density of capillaries in a given vascular bed is proportional to the O2 demand of that tissue.

In spite of the fact that the transmural pressure across the capillary walls is 15-60 mm Hg (depending on the tissue), the stress in the walls of capillaries is relatively small because of their small diameter (Fig. 2). The La Place relationship demonstrates that a small vessel radius results in a small wall stress:

Thus a vessel wall composed solely of a single layered endothelium is still able to contain blood under pressure without bursting (Fig. 3).

Venules have the same basic structure as larger veins, but smaller amounts of vascular smooth muscle in the venule wall.

Movement of substances across capillary walls

Capillary permeability is greater in some tissues than others, e.g. liver capillaries are several times more permeable than muscle capillaries. As a general rule all molecules smaller than proteins move easily across the capillary wall. Most capillary membranes are not permeable to proteins and larger molecules.

The structures of capillary beds relates closely to their functions.

Continuous Capillary wall: The endothelium forms a continuous barrier between blood and interstitial space. Tight junctions (zonula occludens) seal the space between endothelial cells. This type of endothelial wall is seen in tissues in which interstitial fluid concentrations are closely controlled. In muscle there are clefts between the endothelial cells that occupy about 0.02% of the capillary surface. In brain capillaries clefts are nonexistent and the capillaries form the “blood-brain barrier”.

Fenestrated capillary: In these capillaries the endothelial wall has fenestrations (fenestra is Latin for window), between endothelial cells that allow greater permeability to non-lipid soluble substances. In reality the fenestrations are not holes, but very thin membrane segments that filter only large molecules. Fenestrated capillaries are typically found in kidney.

Discontinuous capillary: In these vascular beds there are literally large gaps between endothelial cells. These capillaries are highly permeable, even to large molecules like proteins. Typically seen in liver and spleen.

• Transcapillary movement of water and small lipid-soluble molecules.

Most small molecules may be filtered through capillary pores (clefts) that have diameters of about 4 nanometers (nm). Water, urea, and some other hydrophilic molecules with low molecular weights move across capillary walls at much faster rates than can be accounted for by filtration through clefts. These substances diffuse through capillary membranes at 5000 times the rate that they are filtered through capillary clefts. Diffusion of lipid-soluble substances is not limited to the capillary clefts, rather diffusion occurs through the endothelial cell membranes, hence lipid soluble substances diffuse rapidly through the capillary endothelium. For example, CO2 and O2 are sufficiently lipid soluble that they pass through the endothelial cell membranes (CO2 more readily than O2).

The rate of net diffusion through capillary wall is: directly proportional to the capillary surface area, directly proportional to the concentration difference of the substance across the capillary wall, and inversely proportional to the square root of the molecular weight of the substance.

• Transcapillary Movement of Lipid Insoluble Substances.

Small lipid-insoluble ions (e.g. Na+, Cl-) and molecules like water, glucose, and urea diffuse through capillary clefts so rapidly that the concentration inside and outside the capillary equilibrates shortly after blood enters the capillary. (The “reflection coefficient*” of these molecules is small). Because small molecules diffuse through capillary clefts so readily, their rate of diffusion is limited only by the rate of blood flow and they are “flow-limited.” Larger lipid-insoluble substances diffuse less readily; molecules > 60,000 Daltons rarely get through, i.e., they have a large “reflection coefficient”. Generally, negatively charged proteins like albumin have higher “reflection coefficients” than neutral or positively charged proteins. For large lipid-insoluble molecules, the rate of movement across the capillary is limited by the rate of diffusion itself, i.e. movement is “diffusion-limited.”

• Factors controlling the net rate of movement of fluid across the capillary wall

Diffusion is the primary means of movement of water across the capillary wall. However, diffusion of water out of the capillary is nearly balanced by diffusion of water back into the capillary (Fig. 4).

Net movement of water in and out of the capillary occurs through a different mechanism, called filtration and reabsorption, depending on the direction of the net water movement. Starling summarized the forces that control the net movement of fluid across capillary walls with the following relationship:

For a given tissue, the filtration coefficient, k, is constant under most physiological conditions. It is increased, however, in response to certain toxins or when tissue is injured, especially if burned.

In the renal glomerulus, P_c is great, thus filtration of capillary fluid predominates (allowing for the formation of urine); whereas in the lung P_c is low, thus reabsorption predominates (keeping the volume of the lung interstitium small and the alveoli dry).

An increase in venous pressure results in a net increase in P_c. This, in turn increases net filtration. For example, in a 70 kg person an increase in venous pressure of 10 mmHg for 10 minutes increases net capillary filtration by 340 ml producing an accumulation of interstitial fluid or edema.

Note that a variety of factors could alter the filtration-reabsorption balance of capillaries; including changes in arterial and venous pressures, capillary osmotic pressure, tissue hydrostatic pressure, tissue osmotic pressure, and capillary permeability.

• Role of the lymphatic circulation

Lymphatic capillaries are dead-end vessels interspersed between the vascular capillaries. They lack tight junctions between endothelial cells and therefore are more permeable to proteins than are vascular capillaries. Lymph capillaries drain into larger lymphatic vessels possessing one-way valves that prevent back flow. Lymph passes through lymph nodes before it eventually enters the right and the left subclavian veins.

The lymphatic vessels serve several functions:

• When filtration exceeds reabsorption in a given capillary bed, the excess filtered fluid can be returned to the general circulation through the lymphatic vessels. A volume of fluid approximately equal to the plasma volume is returned to the general circulation each day through the lymphatic vessels. The rate of lymph flow is directly proportional to the rate of net filtration in vascular capillaries, and is increased by better capillary pressure, capillary permeability and decreased oncotic pressure.

• Plasma proteins that pass through the capillary clefts (although small in quantity) are returned to the general circulation through lymphatic vessels. If this did not occur these filtered proteins would accumulate in the interstitial space and eventually exert a significant interstitial oncotic pressure. A quantity of protein equal to 1/4 to 1/2 of the circulating plasma protein is returned to the general circulation each day through the lymphatic vessels.

• As lymph circulates through lymph nodes, foreign particles such as bacteria are removed. In the process, the immune system receives additional exposure to antigens present in these foreign particles.

• Chylomicrons formed in the small intestine in the process of fat digestion are transported to the general circulation in lymphatic vessels.Blockage of lymph vessels prevents filtered capillary fluid from returning to the general circulation, and causes edema to develop.

• Order of magnitude of fluid movements in the microcirculation

Diffusion: At a cardiac output of 5 l/minute, about 7,200 l/day of blood (mostly water) flows through the combined capillary beds. However, experiments employing radioisotope dilution have shown that the total diffusion of water across the capillary bed is much larger, coming to a total of about 432 l/day per 100 grams of tissue. Of this, almost all is reabsorbed making net diffusion of water very small.

Typically, 20 l of water/day are filtered out of the capillaries into the interstitium, and 16-18 l/day are reabsorbed into the capillaries. The difference (net movement) is about 2-4 l/day. The net amount filtered is absorbed into the lymph capillaries and returns via lymph channels to the blood.

• Control of Flow and Pressure in the Microcirculation

Delivery of nutrients is dependent on the volume of blood being delivered to the tissue over time. Therefore control of tissue blood flow is critical. Flow through a vascular bed is a function of the pressure difference along the bed; i.e. hydrostatic pressure at the arterial end of the capillary minus hydrostatic pressure at the venous end. Pressure at the arterial end of the capillary is strongly affected by arteriolar diameter (resistance). A variety of normal and abnormal changes may alter venous pressure, arterial pressure, arteriolar resistance etc. Each can affect the rate of blood flow through the tissues.