818 Gong

to transport oxygen and nutrients to the body tissues,
to transport carbon dioxide and waste products away,
to conduct hormones from one part of the body to another.

Flow (Q) is directly proportional to the difference between input (arterial, Pi)) and output (venous, Po) pressure.

Q ∞ Pi – Po

Flow is proportional to the fourth power of the radius of a vessel

Increased radius = increased flow

Cross-sectional area of the blood stream suddenly change: narrowed (stenotic) cardiac valve or artery (atherosclerosis) or widening of large artery (aneurysm)

Reduced viscosity of blood: anemia

High flow velocities associated with the high cardiac output

Flow is inversely proportional to the length of a vessel

Flow is inversely proportional to the viscosity of the circulating blood

the concentration of red blood cells in the circulation (i.e., the hematocrit);

the concentration of plasma proteins,

the rate of blood flow

Bonding of plasma protein to red blood cells increases viscosity

Plasma proteins, fibrinogen, albumin and globulin, have the ability to bond to the surface of RBCs, possibly by ionic boning.

F = π ΔP r4 / 8 η l

Blood flow is directly proportional to the fourth
power of the radius of the vessel, which demonstrates that the diameter of a blood vessel plays by far the greatest role of all factors in determining blood flow through a vessel.

Poor circulation and blockage of blood in the leg arteries produces an aching, tired, and sometimes burning pain in the legs. This pain is brought on by exercise, and relieved by rest. The limping that occurs from leg cramps is called claudication.

Atherosclerosis is a condition in which fatty material collects along the walls of arteries. This fatty material thickens, hardens, and may eventually block the arteries.

Achieved by rapid changes in local vasodilation or vasoconstriction of the arterioles, metarterioles, and precapillary sphincters, occurring within seconds to minutes to provide very rapid maintenance of appropriate local tissue blood flow.

Slow, controlled changes in flow over a period of days, weeks, or even months. In general, these long-term changes provide even better control of the flow in proportion to the needs of the tissues. These changes come about as a result of an increase or decrease in the physical sizes and numbers of actual blood vessels supplying the tissues.

The growth of new blood vessels - is an important natural process occurring in the body, both in health and in disease.

Angiogenesis occurs in the healthy body for healing wounds and for restoring blood flow to tissues after injury or insult. In females, angiogenesis also occurs during the monthly reproductive cycle (to rebuild the uterus lining, to mature the egg during ovulation) and during pregnancy (to build the placenta, the circulation between mother and fetus).

1. Diseased or injured tissues produce and release angiogenic growth factors (proteins) that diffuse into the nearby tissues.

2. The angiogenic growth factors bind to specific receptors located on the endothelial cells (EC) of nearby preexisting blood vessels.

3. Once growth factors bind to their receptors, the endothelial cells become activated. Signals are sent from the cell's surface to the nucleus. The endothelial cell's machinery begins to produce new molecules including enzymes.

4. Enzymes dissolve tiny holes in the sheath-like covering (basement membrane) surrounding all existing blood vessels.

5. The endothelial cells begin to divide (proliferate), and they migrate out through the dissolved holes of the existing vessel towards the diseased tissue.

6. Specialized molecules called adhesion molecules, or integrins (avb3, avb5) serve as grappling hooks to help pull the sprouting new blood vessel sprout forward.

7.Additional enzymes (matrix metalloproteinases, or MMP) are produced to dissolve the tissue in front of the sprouting vessel tip in order to accommodate it. As the vessel extends, the tissue is remolded around the vessel
Sprouting endothelial cells roll up to form a blood vessel tube.

8. Individual blood vessel tubes connect to form blood vessel loops that can circulate blood.

9. Finally, newly formed blood vessel tubes are stabilized by specialized muscle cells (smooth muscle cells, pericytes) that provide structural support. Blood flow then begins.

Occurs in diseases such as cancer, diabetic blindness, age-related macular degeneration, rheumatoid arthritis, and more than 70 other conditions.

In these conditions, new blood vessels feed diseased tissues, destroy normal tissues, and in the case of cancer, the new vessels allow tumor cells to escape into the circulation and lodge in other organs (tumor metastases).

Occurs in diseases such as coronary artery disease, stroke, and delayed wound healing.

In these conditions, inadequate blood vessels grow, and circulation is not properly restored, leading to the risk of tissue death.

Therapeutic angiogenesis, aimed at stimulating new blood vessel growth with growth factors, is being developed to treat these conditions.

autoregulation
flow-dependent vasodilation
active hyperemia
reactive hyperemia

neural
hormonal

Most organs and tissues manifest an increased blood flow (hyperemia) when their metabolic activity is increased, this is termed active hyperemia.

Decreased oxygen concentration
Increased carbon dioxide, an end product of oxidative metabolism
Hydrogen ions (decrease in pH), e.g., from lactic acid
Adenosine, a breakdown product of ATP
Potassium ions, accumulated from repeated action potential repolarization
Eicosanoids, breakdown products of membrane phospholipids
Osmolarity, from the breakdown of high-molecular-weight substances
Bradykinin, a peptide generated locally from a circulating protein
Nitric oxide, a gas released by endothelial cells that acts on immediately adjacent smooth muscle.

This is the response of tissue blood flow following a brief period of local ischemia (seconds to minutes).

Reactive hyperemia is often used as a clinical test of the ability of the peripheral circulation to vasodilate.

Increase the time of ischemia = increase the time of additional blood flow to return to homeostatic levels.

Autoregulation refers to the tendency for tissue blood flow to remain constant in the face of changes in local perfusion pressure.

When standing up, arterial pressure to the head and brain decreases, flow initial decreases but then return toward the level before standing up. The opposite occurs in blood flow to legs.

The vascular smooth muscle contracts in response to an increase in transmural pressure stretch and relaxes in response to a decrease in transmural pressure.

This response is independent of endothelium.

The great majority of blood vessels receive sympathetic but not parasympathetic input. With few exceptions (e.g., external genitialia), arteries, arterioles, venules and veins are innervated by postganglionic sympathetic neurons that elicit vasoconstriction when activated.

The substance secreted at the endings of the vasoconstrictor nerves is almost entirely norepinephrine. Norepinephrine acts directly on the alpha adrenergic receptors of the vascular smooth muscle to cause vasoconstriction.

Sympathetic activity geared toward serving systemic needs, whereas the terminal arterioles are more responsive to local paracrine and metabolites and are therefore positioned to serve the needs of individual tissues.

Under normal conditions, the vasoconstrictor area of the vasomotor center transmits signals continuously to the sympathetic vasoconstrictor nerve fibers over the entire body, causing continuous slow firing of these fibers at a rate of about one half to two impulses per second. The continued firing is called sympathetic vasoconstrictor tone. These impulses normally maintain a partial state of contraction in the blood vessels, called vasomotor tone.

An especially important characteristic of nervous control of arterial pressure is its rapidity of response, beginning within seconds and often increasing the pressure to two times normal within 5 to 10 seconds. Conversely, sudden inhibition of nervous cardiovascular stimulation can decrease the arterial pressure to as little as one half normal within 10 to 40 seconds. Therefore, nervous control of arterial pressure is by far the most rapid of all our mechanisms for pressure control.

In most vascular beds, the existence of beta-2 adrenergic receptors on vascular smooth muscle is of little if any importance since the alpha-adrenergic receptors greatly outnumber them. Accordingly, the net systemic effect of epinephrine secretion in the resting individual is vasoconstriction and an increase in total peripheral resistance.

However, the arterioles in skeletal muscle are an important exception. They have large number of beta-2 adrenergic receptors, circulating epinephrine usually causes vasodilation in this vascular bed.

Vasoconstriction

Vasodilation

It is the most powerful vasoconstrictor hormone because it can exert vasoconstriction by multiple independent mechanisms:

direct;
potentiating the constrictor effects of sympathetic activity by inhibiting the reuptake of norepinephrine into postganglionic sympathetic terminals;
eliciting the secretion of endothelin from vascular endothelial cells;
sympathetic activity to the kidneys releases renin, the enzyme that initiates the series of chemical events leading to angiotensin II.

1) at low concentrations, ADH decreases excretion of water by the kidneys (antidiuresis);
2) at higher concentrations, ADH causes potent vasoconstriction (Vesopressin).

1) osmotic concentration of the extracellular fluid;
2) decreased blood volume

Bottom tier: the most basic form of regulation is autoregulation. Resistance vessels react to changes in blood pressure so that blood flow varies little with pressure. Autoregulation is due chiefly to the myogenic response.

Middle tier: the autoregulated flow is increased or decreased by intrinsic regulatory chemicals produced within the tissue. The chief ones are the vasodilators of functional hyperaemia (CO2, lactate, adenosine, K+, phosphate and hyperosmolarity), endothelial secretions (NO, EDHF, prostacyclin, endothelin) and autocoids (histamine, thromboxane and PAF).

Top tier: the highest level of control is extrinsic regulation from outside the tissue by vasomotor nerves and hormones. This brings vascular regulation under the control of the brain.

The structure of veins allows them to be very distensible and capable of accommodating a large volume of blood.

larger lumen
thinner smooth muscle layer
thicker adventitia

the walls of the veins contain smooth muscle innervated by sympathetic neurons. Stimulation of these neurons releases norepinephrine, which causes contraction of the venous smooth muscle , decreasing the diameter and compliance of the vessels and raising the pressure within them.

When the patient stand -->
capillary hydrostatic pressure increase --> filtration of plasma to interstitial --> edema
inadequate diffusion of nutritional material --> muscle pain and weak.

Walking will cause the skeletal muscles to contract and increase VR. Increased VR will decrease blood in the veins which will decrease the pressure in the veins.

During inspiration, diaphragm descends, increasing abdominal pressure and consequently increasing intraabdominal vein pressure. At the same time, the pressure in thorax decreases, thereby decreasing the pressure in the intrathoracic veins and right atrium. The net effect of the pressure changes is to increase the pressure difference between the peripheral veins and the heart and enhanced venous return.

Respiration would reverse this effect if not for the venous valves.

The valves of the venous system becomes “incompetent” or sometimes even are destroyed.

Large, bulbous protrusions of the veins beneath the skin of the entire leg.

This is transport of nutrients to the tissues and removal of cell excreta.

In general, each artery entering an organ branches six to eight times before the arteries become small enough to be called arterioles (10 to 15 micrometers). Then the arterioles branch two to five times , reaching diameter of 5 to 9 micrometers at their ends where they supply blood to capillaries.

At each point where each true capillary originates from a metarteriole, a smooth muscle fiber usually encircles the capillary, This is called the precapillary sphincter. This sphincter can open and close the entrance to the capillary.

The venules are larger than the arterioles and have a much weaker muscular coat.

the precapillary sphincters are in close contact with the tissues they serve. Therefore, the local conditions of the tissues—the concentrations of nutrients, end products of metabolism, hydrogen ions, and so forth—can cause direct effects on the vessels in controlling local blood flow in each small tissue area.

Composed of a unicellular layer of endothelial cells and is surrounded by a very thin basement membrane on the outside of the capillary.

The total thickness of the capillary wall is only about 0.5 micrometer.

The internal diameter of the capillary is 4 to 9 micrometers, barely large enough for red blood cells and other blood cells to squeeze through.

The thin-slit, curving channel that lies between adjacent endothelial cells.
The endothelial cells generally contain large numbers of endocytotic and exocytotic vesicles, and sometimes these fuse to form continuous fused-vesicles channels across the cell.

The capillary is the primary point exchange between the blood and the interstitial fluid.

Intercellular clefts assist the exchange.

Capillary walls are a single endothelial cell in thickness.

There are far more capillaries compared to any other microvessels, therefore the area available for exchange is greatest in the capillary networks

The capillaries have the greatest surface-to-volume ratio

The velocity of flow is slowest in the capillaries

The spaces between cells are collectively called the interstitum. The fluid in these spaces is the interstitial fluid.

1) collagen fiber bundles
2) proteoglycan filaments

The collagen fiber bundles extend long distances in the interstitium. They are extremely strong and therefore provide most of the tensional strength of the tissues. The proteoglycan filaments, however, are extremely thin coiled or twisted molecules. They form a mat of very fine reticular filaments aptly described as “brush pile”.

1). Lipid-soluble substances can diffuse directly thorough the cell membrane of the capillary endothelium (O2 and CO2)

2) Water-soluble, non-lipid-soluble substances diffuse only through intercellular “pores” in the capillary membrane

3) Vesicular transport: may be through which large molecules, such as whole proteins, are transported across the capillary endothelium.

Qx: diffusion rate
A: diffusion area
Px: permeability coefficient of the substance
Cpx: concentration of substance in plasma
Cifx: concentration of substance in interstitial fluid

Substances that are highly lipid soluble, such as oxygen and CO2, have essentially the whole endothelial surface available for diffusion, whereas diffusion of substances that are water-soluble is restricted to functional pores within the capillaries. Therefore, the rates of transports of lipid soluble substances are many times faster than the rates for water-soluble substances, such as sodium ions and glucose.

For both lipid- and water-soluble substances, the surface area for exchange is controlled by adjusting the number of capillaries through which blood is flowing.

Is a measure of the ease with which vascular endothelium permits passage of the substance.

The magnitude of Px is an interactive effect of the capillary endothelium and the diffusing substance.

In the brain, the junctions between the capillary endothelial cells are mainly “tight” junctions that allow only extremely small molecules such as water, oxygen, and carbon dioxide to pass into or out of the brain.

In the liver, the opposite is true. The clefts between the capillary endothelial cells are wide open, so that almost all dissolved substances of the plasma, including the plasma proteins, can pass from the blood into the liver tissues.

The pores of the gastrointestinal capillary membranes are midway between those of the muscle and those of the liver.

Lipid-soluble vs. water-soluble: Solutes that are highly lipid-soluble penetrate the lipid endothelium quite easily and hence have a high permeability factor. At the other extreme, water-soluble substances, such as sodium, potassium, and chloride, have extremely low permeabilities due to the fact that their diffusion is restricted to the aqueous medium of the endothelial junctions.

Size of the water-soluble substance.

If endothelial permeability is high, solute crosses the capillary wall so quickly that the plasma equilibrates with the pericapillary interstitial fluid before the end of the capillary.

Lipophilic solutes: O2, CO2

The plasma solute concentration has not equilibrated with the pericapillary space by the end of the capillary, and the concentration profile is relatively flat.
In diffusion-limited exchange, solute transfer is limited by endothelial permeability rather than by solute delivery rate, i.e. flow.
Medium-to-large lipophobic solutes: inulin, vitamin B12
Small solutes, urea and glucose, when the transit time is shortened by high blood flows

Capillary recruitment:
reduces the radius of the Krogh cylinder and hence diffusion distance enhances diffusional surface area
increased flow may increase endothelial permeability

Fall in tissue glucose Steeper concentration gradients, raises the fractional extraction and arteriovenous concentration difference

Increased blood flow:
prevents a major fall in the mean intracapillary plasma concentration

Capillary recruitment:
reduces the radius of the Krogh cylinder and hence diffusion distance enhances diffusional surface area
increased flow may increase endothelial permeability

Fall in tissue glucose Steeper concentration gradients, raises the fractional extraction and arteriovenous concentration difference

Increased blood flow:
prevents a major fall in the mean intracapillary plasma concentration

Functions more in the regulation of plasma volume than it does in the exchange of nutrients.

The endothelial cell junctions of capillaries behave as filters that allow the flow of plasma water and all dissolved solutes, such as electrolytes and glucose, but considerably inhibit the passage of suspended colloids, such as the large-molecular-weight proteins.

The capillary pressure (Pc)

The interstitial fluid pressure (Pif)

The capillary plasma colloid osmotic pressure (COPp or Πp)

The interstitial fluid colloid osmotic pressure (COPif)

Which tends to force fluid outward through the capillary membrane.

Which tends to force fluid inward through the capillary membrane when Pif is positive but outward when Pif is negative.

Which tends to cause osmosis of fluid inward through the capillary membrane.

Which tends to cause osmosis of fluid outward through the capillary membrane.

Because the proteins are the only dissolved constituents in the plasma and interstitial fluids that do not readily pass through the capillary pores, it is the proteins of the plasma and interstitial fluids that are responsible for the osmotic pressures on the two sides of the capillary membrane. To distinguish this osmotic pressure from that which occurs at the cell membrane, it is called either colloid osmotic pressure or oncotic pressure.

Increased capillary filtration coefficient
Increased capillary hydrostatic pressure
Decreased plasma colloid osmotic pressure

1) Local dilatation of the resistance vessels: vasodilation --> increased capillary pressure --> filtration of plasma into interstitial space
2) Capillary recruitment: enhances O2 transport, but it raises the capillary filtration capacity too.
3) Increased interstitial osmolarity: the release of small solutes such as lactate and K+ into the interstitial space by the contracting muscle fibers raises the interstitial fluid osmolarity by 7-10%.
The osmolarity of the sarcoplasm too increases during muscle contraction --> intracellular swelling

vasodilation increased capillary pressure filtration of plasma into interstitial space

enhances O2 transport, but it raises the capillary filtration capacity too.

the release of small solutes such as lactate and K+ into the interstitial space by the contracting muscle fibers raises the interstitial fluid osmolarity by 7-10%.
The osmolarity of the sarcoplasm too increases during muscle contraction intracellular swelling

Special structure of the lymphatic capillaries that permits passage of substances of high molecular weight into the lymph.

Most of the fluid filtering from the arterial ends of blood capillaries is reabsorbed back into the venous ends of the blood capillaries; but on the average, about 1/10 of the fluid instead enters the lymphatic capillaries and returns to the blood through the lymphatic system rather than through the venous capillaries. The total quantity of all this lymph is normally 2 to 3 liters each day.

The concentration of proteins in the interstitial fluids;
The volume of interstitial fluid;
The interstitial fluid pressure.

The fluid that returns to the circulation by way of the lymphatics is extremely important because substances of high molecular weight, such as proteins, cannot be absorbed from the tissues in any other way.

Lymphatic pump

External intermittent compression of the lymphatics

when a collecting lymphatic or larger lymph vessel becomes stretched with fluid, the smooth muscle in the wall of the vessel automatically contracts. Furthermore, each segment of the lymph vessel between successive valves functions as a separate automatic pump

contraction of skeletal muscle
movement of the parts of the body and others

peripheral resistance and blood flow.

venous return and cardiac output

capillary blood flow

Vascular smooth muscle contract very slowly. The shortening velocity is about 1/10th that of skeletal muscle

The degree of shortening can be substantial due to the length of the contractile filaments.

The sustained nature of vascular smooth muscle is remarkable. Many arterioles and arteries maintain a state of partial contraction throughout life. This sustained tone is a crucially important property because dilatation, and with it the ability to raise blood flow, is achieved entirely through a reduction in the tone.

1. Serve as a physical lining that blood cells do not normally adhere to in heart and blood vessels. Endothelial cells can express some adhesion molecules to recruit leukocytes.


2. Serve as a permeability barrier for the exchange of nutrients, metabolic end products, and fluid between plasma and interstitial fluid; regulate transport of macromolecules and other substances.

3. Secret paracrine agents that act on adjacent vascular smooth muscle cells; including vasodilators—prostacyclin and nitric oxide (endothelium-derived relaxing factor, EDRF)-and vasoconstrictors-notably endothelin

NO and PGI2 and EDHF are released

eNOS: endothelium NOS
iNOS: inducible NOS
nNOS: neuronal NOS

1) Substances such as acetylcholine, bradykinin, histamine, insulin, and substance P;

2) shearing forces acting on the luminal surface of vascular endothelium. 

These stimuli increase cytoplasmic free calcium and activate NOS.

cytokines (e.g., tumor necrosis factor,interleukins)
bacterial endotoxins (e.g., lipopolysaccharide). -->

Induction of iNOS -->

NO production that may be more than a 1,000-fold greater than that produced by eNOS

Drugs that inhibit the breakdown of cGMP potentiate the effects of NO-mediated actions on the target cell.

**Important: do not use together with Nitroglycerin (= decrease blood pressure too much)

Inhibitors of cGMP-dependent phosphodiesterase -->

increased cGMP -->

sustained vasodilation

Agonist --> activate PLC --> IP3 --> increased cystolic Ca --> bind to calmodulin --> activate kinases to turn on eNOS --> conversion of L-Arginine to citruline and NO --> can go thru endothelial cell --> effect guanylyl cyclase --> vasodilation

Sheer stress due to blood flow --> activate eNOS

Notice that increase in Ca **when in endothelial cells** causes vasodilation. Increase in Ca in smooth muscle causes constriction

Myogenic mechanism

Metabolite theory

The degree of arteriolar adjustment would be the collective effect of metabolic and myogenic mechanisms. As a result of these adjustments, both tissue blood flow and local capillary pressure would tend to be maintained.

Vessels dilate in response to increased flow

Skeletal muscle contraction will cause the smooth muscle to dilate prior to increased blood flow.

Sheer stress caused by blood flow causes the endothelial cells to react and dilate to accommodate flow

Sheer stress caused by blood flow causes the endothelial cells to react and dilate to accommodate flow

The capillary pressure (Pc)

The interstitial fluid colloid osmotic pressure (COPif)

The interstitial fluid pressure (Pif) WHEN NEGATIVE

The capillary plasma colloid osmotic pressure (COPp or Πp)

The interstitial fluid pressure (Pif) WHEN POSITIVE

TRUE

Varicosities = enlargement at nerve terminal
Stores synaptic vessels (with stuff such as noradreneline)

Single smooth muscle cell can receive input from multiple nerve endings

Varicosities = enlargement at nerve terminal
Stores synaptic vessels (with stuff such as noradreneline)

In smooth muscle, Ca2+ does not go straight to troponin, but binds to calmodulin --> activa myosin light chain kinase --> phosphorylate myosin head --> contraction

Initial phase of contraction, the actin myosin bridge lock --> maintian smooth muscle tone over prolonged time at lower energy cost

Rho kinase and phosphatase inhibitory proteins will lead to the inhibition of phosphatase which will lead to enhanced sensitivity of myosin towards Ca2+

Epi/NE/Angiotensin II/ADH --> G protien --> open ligand gated Ca channel -->Ca influx --> Depolarization --> open voltage gated Ca channel --> additional Ca influx
G protein also activate phospholipase C --> make IP3 --> bind to SR --> additional cytoplasmic Ca --> make DAG --> activate PKC

All this additional Ca can bind to calmodulin to bind to myosin light chain kinase to phosphorylate the myosin --> initiate contraction

Vasodialtion = inhibition of methods that cause contraction
Activate Ca pump in SR --> sequester cystolic Ca
Activate Ca pump in plasma membrane --> pump Ca out to extracellular phase

cAMP receptor (g protein receptor) --> activate adenylate cyclase --> increase cAMP --> activate PKA --> phosphorylate the Ca pumps
NO --> guanylate cyclase --> increase cGMP --> activate PKG --> activate calcium pump

Release NO in coronary artery smooth muscle --> Activate soluble guanylate cyclase --> cGMP --> Relax spasmed coronary artery --> Relieves chest pain

Noradreneline increase Ca activation and then also maintains force at a high level even after Ca channels have sensitized and decreased their levels
** calcium sensitization = Noradreneline makes the myosin actin filament more sensitive to Ca
Important for maintaining vascular tone. Even at rest, smooth muscles in vessels have a partial constriction = it’s tone. The noradreneline making the muscle more sensitive to Ca allows the maintained force