L16 CVS Physiology 8 Microcirculation (solute exchange, diffusion)

Overview

This lecture covers how the microcirculation is built and how it does its two jobs: moving solutes by diffusion and moving fluid by bulk flow. It works through the branching structure from arteriole to capillary to venule, capillary wall structure and the three structural classes of capillary, the physics of why a thin-walled capillary survives arterial-level pressure, the factors that govern diffusion of solutes across the wall (Fick’s law, molecule type and size, metabolic demand, capillary recruitment), and finally the Starling principle of fluid exchange, including the four pressures that set filtration/absorption balance and what goes wrong with that balance in oedema and shock.

Design of the microcirculation

The microcirculation’s core functions: transport nutrients to tissue cells, and remove cellular waste products. Each organ’s microcirculation is specifically organised for its own needs.
Branching pathway: arteries branch repeatedly into arterioles (5-100 µm diameter); arterioles branch 2-5 more times to 10-30 µm before feeding capillaries (4-8 µm diameter). Blood enters a capillary via the arteriole and leaves via the venule.
Arterioles can feed capillaries directly, or via metarterioles; metarterioles can also connect straight to venules, acting as a shunt bypassing the capillary bed.
Pericytes are vascular mural cells wrapped around the basement membrane/endothelial cell of capillaries.
Vessel diameter (arteriolar tone) is set by five converging inputs, each with a constrictor and dilator arm:
- Sympathetic activity (constrictor and dilator branches)
- Vasoactive metabolic factors: dilators - CO2, lactate, adenosine; constrictor - O2
- Hormonal factors: constrictors - adrenaline (α-receptors), angiotensin II, vasopressin (ADH); dilators - adrenaline (β-receptors), atrial natriuretic peptide (ANP)
- Endothelial secretions: constrictor - endothelin; dilators - nitric oxide, prostacyclins, adenosine
- Myogenic autoregulation of blood pressure
Capillaries are the primary site of exchange. As a bed, they have the largest total cross-sectional area (~3000 cm²) and the lowest mean blood velocity of any vessel level - an inverse relationship between cross-sectional area and velocity - giving a long capillary transit time (~0.5-2 s) that allows time for exchange.
Structurally, going from large artery to arteriole to capillary there is progressive loss of smooth muscle and elastic layers: large artery (multiple smooth muscle/elastic/connective tissue layers + endothelium) > arteriole (smooth muscle + endothelium) > capillary (basement membrane + single endothelial cell layer only, no smooth muscle).
Capillary structure: thin-walled tube of endothelial cells without smooth muscle, covered by a basement membrane; 500-1000 µm long, 4-8 µm wide, total wall thickness ~0.5 µm. Adjacent endothelial cells are not tightly attached - they are separated by water-filled “intercellular clefts” that allow passage of water and small lipid-insoluble solutes (glucose, amino acids, drugs). Endothelial cells also contain endocytotic and exocytotic vesicles.
At any moment, 6% of total circulating blood is within capillaries; this “nutritional blood flow” carries out exchange of nutrients, metabolic end products and secretions.
An adult has an estimated 25,000 miles of capillaries; density depends on tissue metabolic demand - skeletal muscle has 300-1000 capillaries/mm², while myocardium and brain (highly metabolically active) have ~3000 capillaries/mm².
Law of Laplace: $T = P \times r$ , where T = wall tension (the tendency of the vessel wall to split), P = transmural pressure, r = vessel radius. The true capillary has no smooth muscle and cannot actively constrict, yet withstands ~25-35 mmHg without bursting despite an extremely thin wall.
Worked comparison: aorta radius ~1 cm (1,000,000 µm), pressure ~100 mmHg; capillary radius ~7-8 µm, pressure ~25 mmHg. Capillary pressure is only 25% of aortic pressure, but because radius enters the Laplace equation, capillary wall tension is about 12,000-fold lower than in the aorta. The narrow capillary lumen is what protects it from bursting under pressure.

Capillary structural classes

Three classes of capillary, differing in how permeable/leaky the endothelial lining is:

Continuous capillaries - moderate permeability, tight/continuous endothelial lining with few gaps. Found in brain and nervous system (blood-brain barrier, very tight), skeletal muscle, myocardium, lungs, skin, fat and connective tissue.
Fenestrated capillaries - rapid filtration/high water permeability via pores (fenestrations) perforating the endothelial cells. Found in exocrine glands (e.g. salivary glands), endocrine glands, and other “high water turnover” tissues: kidney, synovial joints, anterior eye, choroid plexus (CSF production), gut mucosa.
Discontinuous capillaries - endothelial gaps over 100 nm wide, allowing passage of large particles/cells. Found in liver, spleen, bone marrow (sinusoids). Liver is the exception where plasma proteins can also diffuse out.

Solute exchange by diffusion

Capillaries have two main functions, each via a different mechanism: fluid exchange (regulating plasma and interstitial fluid volumes) occurs by bulk flow, driven by pressure gradients across the wall and obeying the Starling principle; solute exchange (nutrition of tissue, hormone and drug delivery) occurs by diffusion, driven by concentration gradients across the wall.
Direct evidence: Evans blue dye (a small, lipid-insoluble solute, radius ~1 nm) injected into a perfused frog mesenteric capillary diffuses progressively outward into surrounding tissue over 0-45 seconds; venous capillaries are normally more permeable than arterial capillaries.
98% of nutrient (or drug) transport across the capillary wall is by diffusion.
Lipid-soluble substances, including O2 and CO2, diffuse easily straight through endothelial cells (trans-cellular route).
Ions and polar molecules are poorly lipid-soluble and instead pass through the water-filled intercellular clefts between endothelial cells.
Proteins are usually excluded from passing through these water-filled channels (the liver’s discontinuous capillaries are the exception).
The transcapillary diffusion gradient itself arises from cellular utilisation or production of the diffusing substance: e.g. a muscle cell consumes O2 and glucose and produces CO2 (and ATP, H2O), so O2 and glucose diffuse from capillary blood through interstitial fluid into the cell, while CO2 diffuses in the opposite direction, from cell to interstitial fluid to capillary.
Fick’s Law of Diffusion: $F = \frac{A}{T} D (P_{1} - P_{2})$ , where F = flux (amount flowing), A = surface area, T = membrane thickness, D = diffusion constant, and $P_{1} - P_{2}$ = the concentration (pressure) difference across the membrane. Rate of diffusion is therefore set by surface area, membrane thickness, and the concentration difference between the two sides.

Factors affecting diffusion across capillaries

Type of molecule - determines the anatomical route taken across the wall:
- Lipid-soluble (O2, CO2): trans-cellular route, straight through the endothelial cell membrane.
- Small non-lipid-soluble (glucose, salts, water): intercellular cleft and the fenestral route (via aquaporin-1 channels).
- Large non-lipid-soluble (proteins): trans-endothelial channels, vesicular transport, or (in inflammation) large gaps that open between cells.
Molecule size - permeability is inversely related to molecular weight (skeletal muscle capillary data): water (MW 18, permeability 1.00), NaCl (58.5, 0.96), urea (60, 0.8), glucose (180, 0.6), sucrose (342, 0.4), inulin (5,000, 0.2), myoglobin (17,600, 0.03), haemoglobin (68,000, 0.01), albumin (69,000, 0.001). Low molecular weight means high permeability; high molecular weight means low permeability.
Metabolic demand:
- A. During heavy exercise, O2 transport from blood to muscle can increase up to 40-fold, through a linked sequence: increased tissue O2 consumption lowers interstitial concentration -> this widens the concentration gradient -> increased blood flow during exercise raises/maintains capillary O2 concentration along the capillary’s length (declining only modestly from ~95 mmHg at the arterial end to ~40 mmHg at the venous end) -> together these drive the large rise in diffusion.
- B. Recruitment of previously closed capillaries increases the total surface area available for diffusion and shortens the diffusion distance from capillary to tissue.

Fluid exchange: the Starling principle

The Starling principle (Ernest Starling, 1896): capillary fluid exchange depends on the balance between hydrostatic pressure (exerted by blood in the capillary, i.e. capillary pressure) and oncotic pressure (colloid osmotic pressure, exerted by plasma proteins).
Four pressures determine the net filtration rate:
- $P_{C}$ - capillary hydrostatic pressure (outward force)
- $π_{C}$ - osmotic force from plasma protein concentration (inward force)
- $P_{I F}$ - interstitial fluid hydrostatic pressure
- $π_{I F}$ - osmotic force from interstitial fluid protein concentration (outward force)
- Net filtration pressure $= P_{C} + π_{I F} - P_{I F} - π_{C}$
Worked values along a single capillary:
- Arterial end: $P_{C} = 35$ , $π_{C} = 28$ , $P_{I F} = 0$ , $π_{I F} = 3$ -> NFP $= 35 + 3 - 0 - 28 = 10$ mmHg, favouring filtration.
- Venous end: $P_{C} = 15$ , $π_{C} = 28$ , $P_{I F} = 0$ , $π_{I F} = 3$ -> NFP $= 15 + 3 - 0 - 28 = - 10$ mmHg, favouring absorption.
Graphically, capillary hydrostatic pressure falls steeply along the capillary’s length (35 -> 15 mmHg) while oncotic pressure stays roughly flat (~25 mmHg). Where capillary pressure exceeds oncotic pressure (arteriolar half), fluid is filtered out of plasma (net loss); where oncotic pressure exceeds capillary pressure (venular half), fluid is reabsorbed into plasma (net gain). These two areas are approximately equal, so there is no net fluid change over the whole capillary length.
In well-perfused capillaries overall, the force balance is: outward forces - mean capillary pressure 17.3 mmHg, negative interstitial free fluid pressure 3.0 mmHg, interstitial fluid colloid osmotic pressure 8.0 mmHg (total outward 28.3 mmHg) - versus inward force - plasma colloid osmotic pressure 28.0 mmHg (total inward 28.0 mmHg) - giving a small net outward force of 0.3 mmHg. This small excess filtrate is normally returned to the circulation via the lymphatic system.

Capillary filtration is altered in several clinical conditions (exact oncotic pressure baseline values for panels A-D were shown only graphically on the slide, not numerically labelled, so they are described qualitatively here):

Inflammatory responses: capillary pressure starts very high (~40 mmHg) and falls steeply; oncotic pressure stays roughly flat (~25 mmHg); net loss from plasma dominates across most of the capillary.

Haemorrhage/shock: capillary pressure starts low (~28 mmHg) and falls only gently to ~15 mmHg; oncotic pressure flat at ~25 mmHg; net gain to plasma dominates across most of the capillary.

Heart failure: capillary pressure starts at 35 mmHg and falls only gently, staying above oncotic pressure (~25 mmHg) for most of the capillary length; net loss from plasma dominates.

Hepatic failure: capillary pressure falls from 35 to 15 mmHg as normal, but oncotic pressure is lower than normal (drawn at ~20 rather than ~25 mmHg because plasma protein, e.g. albumin, production is impaired); a very large net loss from plasma results.

Clinical significance of fluid exchange

An excessive rate of capillary fluid filtration from plasma into the interstitium causes fluid accumulation in tissue - oedema. Causes include lymphatic disorder, cardiac failure, renal failure, pleural effusions, peritoneal swelling (ascites), and joint effusions.
Example: lymphedema following surgery to remove breast cancer (lymph node/vessel disruption impairs lymphatic return of filtered fluid).
Fluid transfer across the capillary wall in the opposite direction (net absorption into plasma) is also medically important, e.g. in haemorrhage, and in the normal functioning of renal and intestinal mucosa.

Self-test

State the two main functions of capillaries and the mechanism that drives each.
Describe the branching pathway blood takes from artery to capillary and back to vein, including the role of metarterioles as a shunt.
What is a pericyte, and where is it located relative to the capillary wall?
Explain why capillaries have the largest total cross-sectional area but the lowest blood velocity of any vessel level, and why this matters for exchange.
List the five categories of factors that regulate vessel diameter, giving one vasodilator and one vasoconstrictor example from each category where given.
Using the Law of Laplace, explain why a capillary does not burst despite its extremely thin wall and relatively high internal pressure.
Distinguish continuous, fenestrated and discontinuous capillaries in terms of structure and give one tissue location for each.
Describe the structure of the capillary wall (cell layers, thickness, intercellular clefts) and what the intercellular clefts allow through.
What proportion of nutrient/drug transport across capillaries occurs by diffusion, and by which route do lipid-soluble gases cross the wall?
Describe the anatomical routes taken by small non-lipid-soluble molecules versus large non-lipid-soluble molecules (e.g. proteins) crossing the capillary wall.
State Fick’s law of diffusion and explain what determines the rate of diffusion according to it.
Using the skeletal muscle capillary permeability data, describe the relationship between molecular weight and permeability, citing two examples from the table.
Describe the three-step sequence by which heavy exercise increases O2 diffusion from capillary to muscle up to 40-fold.
Explain how recruitment of previously closed capillaries increases diffusion capacity.
State the Starling equation for net filtration pressure and use it to explain why filtration dominates at the arterial end of a capillary while absorption dominates at the venous end.
A patient develops a swollen arm after axillary lymph node surgery for breast cancer. Explain the physiological mechanism causing this swelling.
Distinguish how the balance of capillary filtration and absorption is altered in inflammation, haemorrhage/shock, heart failure and hepatic failure.

Answers

Reveal answers

Fluid exchange (regulating plasma and interstitial fluid volumes) occurs by bulk flow, driven by pressure gradients across the capillary wall (Starling principle). Solute exchange (nutrition, hormone/drug delivery) occurs by diffusion, driven by concentration gradients across the wall.

Arteries branch repeatedly into arterioles (5-100 µm), which branch 2-5 more times to 10-30 µm before feeding capillaries (4-8 µm); blood enters via the arteriole and leaves via the venule. Arterioles can feed capillaries directly or via metarterioles, and metarterioles can also connect straight to venules, bypassing the capillary bed as a shunt.

A pericyte is a vascular mural cell wrapped around the basement membrane and endothelial cell of a capillary.

Capillaries collectively have the largest total cross-sectional area (~3000 cm²) of any vessel level, and cross-sectional area and velocity are inversely related, so velocity is lowest there. This gives a long transit time (0.5-2 s) that allows sufficient time for diffusion-based exchange.

Sympathetic activity (constrictor/dilator branches); vasoactive metabolic factors (dilators: CO2, lactate, adenosine; constrictor: O2); hormonal factors (constrictors: adrenaline via α-receptors, angiotensin II, vasopressin/ADH; dilators: adrenaline via β-receptors, ANP); endothelial secretions (constrictor: endothelin; dilators: nitric oxide, prostacyclins, adenosine); myogenic autoregulation.

By the Law of Laplace ( $T = P \times r$ ), wall tension depends on both pressure and radius. Although capillary pressure (~25 mmHg) is high relative to the vessel’s size, the capillary’s radius is extremely small (~7-8 µm vs ~1 cm in the aorta), so wall tension is about 12,000-fold lower than in the aorta - the narrow lumen is what protects the thin wall from bursting.

Continuous: tight, few gaps, moderate permeability; found in brain/CNS (blood-brain barrier), skeletal muscle, myocardium, lungs, skin. Fenestrated: pores through the endothelium giving rapid filtration/high water permeability; found in exocrine/endocrine glands, kidney, choroid plexus. Discontinuous: large gaps (>100 nm) between endothelial cells; found in liver, spleen, bone marrow.

A thin-walled tube of endothelial cells without smooth muscle, covered by a basement membrane, ~500-1000 µm long, 4-8 µm wide, wall thickness ~0.5 µm. Adjacent cells are not tightly attached but separated by water-filled intercellular clefts, which allow water and small lipid-insoluble solutes (glucose, amino acids, drugs) through.

98% of nutrient/drug transport is by diffusion. Lipid-soluble gases (O2, CO2) cross via the trans-cellular route, straight through the endothelial cell membrane.

Small non-lipid-soluble molecules cross via the intercellular cleft and the fenestral route (aquaporin-1 channels). Large non-lipid-soluble molecules (proteins) cross via trans-endothelial channels, vesicular transport, or large gaps that open between cells during inflammation.

$F = \frac{A}{T} D (P_{1} - P_{2})$ : flux (F) is set by surface area (A), membrane thickness (T), a diffusion constant (D), and the concentration/pressure difference across the membrane ( $P_{1} - P_{2}$ ). Rate of diffusion is therefore governed by surface area, thickness, and the concentration difference.

Permeability falls as molecular weight rises. E.g. water (MW 18) has permeability 1.00, while albumin (MW 69,000) has permeability only 0.001 - low molecular weight solutes cross far more readily than high molecular weight ones.

(1) Increased tissue O2 consumption lowers the interstitial O2 concentration; (2) this increases the concentration gradient between capillary and tissue; (3) increased blood flow during exercise raises/maintains capillary O2 concentration along the capillary’s length, together driving up to a 40-fold increase in O2 diffusion.

Opening previously closed capillaries increases the total surface area available for diffusion and shortens the diffusion distance from any capillary to the surrounding tissue, both of which increase diffusion (per Fick’s law).

Net filtration pressure $= P_{C} + π_{I F} - P_{I F} - π_{C}$ . At the arterial end, capillary hydrostatic pressure (35 mmHg) is high relative to oncotic pressure (28 mmHg), giving a net outward pressure of 10 mmHg favouring filtration. At the venous end, capillary pressure has fallen (15 mmHg) below oncotic pressure (28 mmHg), giving a net inward pressure of -10 mmHg favouring absorption.

Lymph node/vessel disruption from the surgery impairs lymphatic drainage of the small amount of fluid that normally filters out of capillaries and is returned via the lymphatics; without that return, filtered fluid accumulates in the interstitium as oedema (lymphedema).

Inflammation: capillary pressure starts very high (~40 mmHg) and falls steeply while oncotic pressure stays ~25 mmHg, so net loss from plasma dominates. Haemorrhage/shock: capillary pressure starts low (~28 mmHg) and falls only gently to ~15 mmHg, so net gain to plasma dominates. Heart failure: capillary pressure starts at 35 mmHg and stays above oncotic pressure for most of the capillary’s length, so net loss from plasma dominates. Hepatic failure: capillary pressure falls from 35 to 15 mmHg as normal, but oncotic pressure is lower than normal (impaired protein production), so a very large net loss from plasma results.

tags	cvs, lecture, physiology
aliases	L16 CVS Physiology 8 Microcirculation (solute exchange, diffusion)

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