Adelina Vlad, MD Ph

The Circulation- part 2 -

Physical Characteristics of the

Vascular System

Mean linear velocity of blood flow

is inversely proportional to

aggregate vascular cross-sectional

area:

- 21 cm/s in the aorta

- 0.03 cm/s in the capillaries,

under resting conditions

- 14 cm/s in venae cavae

Distribution

of blood

Aggregate Cross-Sectional

Area (cm2)

Pressures Along the Vascular System High pressure zone: contracting LV systemic arterioles

Low pressure zone: systemic capillaries right heart

pulmonary circulation left atrium LV in relaxed state

Normal blood pressures in the different portions of the circulatory

system when a person is lying in the horizontal position

Pulsatile

Mean value:

100 mmHg

Average

pressure

17 mm Hg

0 mm

Hg

LV

Pulsatile

Mean value:

16 mmHg

Average

pressure

7 mm Hg

RV

Structure – Function Relationship

(elastic fibers

dominance)(collagen fibers

dominance)

Systemic Veins Allow blood return to the heart

By contracting or enlarging their lumen, veins can

adjust the amount of blood returned to the heart and influence

the cardiac output (Frank-Starling mechanism)

store or mobilize large amounts of blood in accordance to

the physiologic needs

Veins are compliant structures, with low resistance and large

capacitance they can accommodate important amounts of

blood for a tiny increase in pressure

Total cross-section area of veins is larger than similar degrees of

arborisation in the arterial system, therefore blood advances with

a much lower velocity through the veins

Pressure in the venous bed decreases from periphery

towards atria, generating a pressure gradient that allows blood

to return from tissues to the heart

venous return is favored by an increase of pressure in the

periphery and a lowering of pressure on the way to the heart

Central Venous Pressure = The pressure in the right atrium, the endpoint of systemic

venous return

It is regulated by a balance between

the ability of the heart to pump blood out of the right atrium

and ventricle into the lungs

the tendency for blood to flow from the peripheral veins into

the right atrium

Central Venous Pressure Normal value: about 0 mm Hg;

Can increase to 20 - 30 mm Hg due to

serious heart failure

massive transfusion

Can decrease to about -3 - -5 mm Hg, which is the pressure in

the chest cavity that surrounds the heart

when the heart pumps with exceptional vigor

when blood flow from the peripheral vessels to the heart is

greatly depressed (severe hemorrhage)

Peripheral venous pressure is

increased by:

raise of RA pressure above +4 to

+6 mm Hg (heart failure) blood

begins to back up into the veins

high intra-abdominal pressure

(pregnancy, abdominal tumors,

ascites) pressure in the legs

veins must surpass intra-abdominal

pressure

hydrostatic pressure when there

is a difference in height along the

veins

Venous resistance

Could be very low

Large veins do usually offer some

resistance to blood flow due to

compression by the surrounding

tissues:

veins from the arms over the first rib

intra-abdominal veins by different

organs and by the intra-abdominal

pressure

neck veins often collapse under the

push of the atmospheric pressure

Venous return can be increased by:

Increased blood volume

Decreased pressure toward the heart

During inspiration

By low pressures in the right atrium provided by a good RV

performance

Increased pheripheral venous pressure:

increased large vessel tone throughout the body with resultant

increased peripheral venous pressures

dilatation of the arterioles which decreases the peripheral

resistance and allows rapid flow of blood from the arteries into

the veins

The activity of the “venous pump”

Changing body position from standing/sitting to horizontal or by

rising the legs while lying down

Venous Valves and the Venous Pump

the venous pressure in the feet

of a walking adult is less than

+20 mm Hg, whereas in the

standing, immobile position it

would be + 90 mm Hg

Venous valve incompetence

causes varicose veins

Veins below the heart level are equipped with valves that allow

blood to flow in only one direction – towards the RA

When veins below the heart are compressed by contracting

muscles or pulsing arteries, due to the valves inside the veins

the blood is pushed forward to the RA = “venous pump” or

“muscle pump”

Estimation of Venous Pressure Clinical estimation - by simply observing the degree of

distention of the peripheral veins: external jugular veins begin to

protrude at + 10 mm Hg RA pressure

Direct measurement of

Peripheral venous pressure – with a needle connected to a pressure

recorder

RA pressure – with central venous catheters

Zero height pressure reference

level

- near the level of the tricuspid valve

- here the pressure is unaffected by

changes of body posture because

the heart acts as a feedback

regulator of pressure

Reservoir Function of the Veins More than 60% of all the blood in the circulatory system is

usually in the veins

When circulating blood volume decreases, nervous reflexes

determine the mobilization of blood from the reservoirs of the

body venous reservoir can cover a loss of up to 20% of the

total blood volume

Specific blood reservoirs

the venous sinuses of the spleen, 100 ml

the venous sinuses of the liver, several hundreds ml

the large abdominal veins, 300 ml

the venous plexus beneath the skin, several hundreds ml

Limphatic System

Limphatic System

Filtration at the arteriolar end of the

capillary exceeds reabsorbtion at the

venular end by 2 – 3 l/day this

excess liquid together with proteins

and other large molecules from the

interstitium move into the lymphatics

Limphatics – arise at the interstitium as

small thin-walled channels larger

vessels the thoracic duct and the

right lymph duct drain into the left

and right subclavian veins

Limphatics are absent from some

tissues (myocardium, brain, bones...)

Structure of Limphatic Vessels Capillaries

- closed ended channels with endothelial cells that are attached

by anchoring filaments to the surrounding connective tissue

- at the junctions of adjacent endothelial cells, the edge of one

endothelial cell overlaps the edge of the adjacent cell forming a

minute valve that opens to the interior of the lymphatic capillary

Larger lymphatic vessels – have walls similar to those of small

veins (endothelium, smooth muscle)

Lymphatic vessels are equipped with valves

Formation of Lymph Lymph as it first enters the terminal lymphatics has almost the

same composition as the interstitial fluid; protein concentration of

about 2 g/dl in most tissues, 6 g/dl in liver and 3-4 g/dl in

intestines 3-5 g proteins/dl in the thoracic duct lymph

Lymphatic system is also one of the major routes for absorption

of nutrients from the gastrointestinal tract, especially for virtually

all fats in food – up to 1-2% fat in the thoracic duct lymph after a

fatty meal

Large particles such as bacteria can enter the lymph, but they

are removed and destroyed as the lymph passes through the

lymph nodes

Rate of Lymph Flow Averages 120 ml/hr or 2 to 3 liters per day

Two primary factors determine lymph flow

1) the interstitial fluid pressure

2) the activity of the lymphatic pump

The interstitial fluid pressure

Increased interstitial fluid pressure increases lymph flow

But only up to the “maximum

lymph flow rate” (plateau) – when

the interstitial fluid pressure

becomes greater than atmospheric

pressure (0 mm Hg), the

increasing tissue pressure also

compresses the outside surfaces

of the larger lymphatics, impeding

lymph flow

Lymphatic Pump Intrinsic pump

When a collecting lymphatic or larger lymph vessel becomes

stretched with fluid, the smooth muscle in the wall of the

vessel automatically contracts

Each segment of the lymph vessel between successive valves

functions as a separate automatic pump

In the thoracic duct, this lymphatic pump can generate

pressures as great as 50 to100 mm Hg

External intermittent compression of the lymphatics

Contraction of surrounding skeletal muscles and intestines

Movement of the parts of the body

Pulsations of arteries adjacent to the lymphatics

Compression of the tissues by objects outside the body

Lymphatic capillary pump

Terminal lymphatic capillaries are tethered to surrounding

connective tissue by means of the anchoring filaments

muscle contraction or swelled interstitium can deform them,

making the openings between the endothelial cells more

patent

The lymphatic capillary endothelial cells also contain a few

contractile actomyosin filaments

Roles of the Lymphatic System

The lymphatic system plays a central role in controlling

1) the concentration of proteins in the interstitial fluids

2) the volume of interstitial fluid

3) the interstitial fluid pressure

All these factors are linked to one another:

Proteins leak from the capillaries into the interstitium

increased interstitial colloid osmotic pressure increased

volume of interstitial fluid increased interstitial fluid pressure

increased limph flow wash-out of interstitial protein and

liquid in excess

= the return of protein and fluid by way of the lymphatic system

balances exactly the rate of leakage of these into the interstitium

from the blood capillaries = steady state

The Microcirculation

The Microcirculation Is the site of the most purposeful function of the circulation:

delivery of nutrients to the tissues and removal of cell excreta

Is defined as the blood vessels from the first-order arterioles to

the first-order venule

Principal components: 1 arteriole – metarteriole (+/-) – network of

capillaries – 1 venule

Structural Particulars Arterioles – inner radius 5 - 25 mm

Inner layer of endothelium

Internal elastic lamina

A single continuous layer of innervated VSMCs

Metarterioles – shorter than arterioles

Similar structure to the arterioles except the VSCMs layer that is

discontinuous and usually not innervated

Precapillary sphincter – small cuff of VSMCs, usually not

innervated but very responsive to local stimuli

Capillaries – inner radius 2 - 5 mm

Single layer of endothelial cells

Basement membrane

Pericytes in some tissues – elongated, branched cells involved in

exchange, growth and repair processes, local control of blood flow

Venules – inner radius 5 - 25 mm

VSCMs layer is discontinuous, innervated

May exchange some solutes across their wall

Metarteriolar Shunt

The Capillaries The walls of the capillaries are extremely thin and highly

permeable

The peripheral circulation of the whole body has about 10 billion

capillaries with a total surface area estimated to be 500 to 700

square meters

The capillaries are the principal site for exchange of

respiratory gases

water

nutrients

waste products

Non-nutritional functions of the capillary flow: plasma

filtration in the glomeruli of the kidney, temperature regulation

in the skin, signalling (delivery of hormones) etc.

Endothelial Cells Have a smooth surface and are very thin (200 – 300 nm)

The cytoplasm is rich in endocytotic (pinocytotic) vesicles that

sometimes form a transendothelial channel transcytosis of

water and water-soluble compounds

Some have fenestrations – cylindrical conduits through the cell

Separated by intercellular clefts (10 – 4 nm wide)

May be linked to one another by tight junctions

May present gaps 100 – 1000 nm wide between adjacent cells

Vesicles, transendothelial channels,

fenestrae, clefts and gaps are part

of permeation across the

endothelial cells

Types of CapillariesBased on their degree of leakiness, the capillaries can be

Continuous capillary - the most common form of capillary; it

has inter-endothelial junctions 10 - 15 nm wide

In the blood-brain barrier - capillaries without clefts and narrow

tight junctions; they don’t permit any paracelullar flow of

hydrophilic solutes

Fenestrated capillary - the endothelial cells are thin and

perforated with fenestrations

Most often they surround epithelia (e.g., small intestine, exocrine

glands) and are present in the glomerular tufts of the kidney

Discontinuous capillary - in addition to fenestrae, these

capillaries have large gaps

- found in sinusoids (e.g., liver)

Flow of Blood in the Capillaries Is intermittent, turning on and off every few seconds or minutes

due to vasomotion = intermitent contraction of the metarterioles

and precapillary sphincters

It is influenced mainly by O2 concentration in the surrounding

interstitium

The parameters of capillary circulation are expressed as average

of the overall capillary activity in each capillary bed:

average rate of blood flow

average capillary pressure

average rate of transfer of substances between the blood of

the capillaries and the surrounding interstitial fluid

Capillary Exchange of Solutes The main mechanism for the transfer of solutes across

capillaries is diffusion

It is governed by:

specific capillary permeability

concentration gradient between capillary and interstitium for

each solute

Fick’s law:

PX = DX/a, the permeability coefficient (cm/s), expresses the ease

with which the solute crosses a capillary by diffusion

Lipophilic solutes (O2, CO2)

can permeate all areas of the capillary membrane

much faster rates of transport through the capillary membrane than the rates for hydrophilic solutes

Hydrophilic solutes need special pathways for passing through

the capillary wall

Paracellular pathway - diffusion through water-filled pores

(clefts, gaps, fenestrae)

Transcytosis - endocytotic vesicles and transendothelial

channels

Paracellular Pathway Hydrophilic solutes smaller than albumin can traverse the

capillary wall by diffusion via a paracellular route: clefts, gaps,

fenestrae

Diffusion through water-filled capillary “pores” depends on the

Size of the polar molecules: permeability coefficient PX falls as

the molecular radius increases

Location: PX increases towards the venular end of the

capillary, where the clefts are wider and the fenestrae are

more common than at its arteriolar end

Electrical charge of small proteins or other macromolecules,

a major determinant of their PX: negative charges in the

diffusion path favor the transit of molecules with positive

charge and impairs the passage of those with negative charge

Solvent drag – a dissolved solute can be carried by the

convective movement of water; has a minor contribution

Transcytosis Is a second mechanism of macromolecular translocation through

capillary, by means of

endocytotic (pinocytotic) vesicles

transendothelial channels formed by the endothelial cells

Characteristics:

It’s not governed by the laws of diffusion

Falls steeply with increases in molecular radius due to steric

hindrance, a process called sieving

Some of the macromolecular cargo may be processed during

transcytosis (e.g., only a tiny part of the endocytosed ferritin is

delivered to the opposite side of the cell)

It’s less prominent in brain capillaries lower permeability of

the blood-brain barrier for macromolecules

Interstitium Spaces between cells are collectively called the interstitium

Interstitium contains two major types of solid structures:

collagen fiber bundles and proteoglycan filaments (98%

hyaluronic acid and 2% protein)

The interstitial fluid is derived by

filtration and diffusion from the

capillaries the same components

as plasma but with much lower

concentrations of proteins

Most of it is entrapped within

proteoglycan filaments tissue gel;

diffusion through the gel occurs about

95 – 99% as rapidly as it does through

free fluid

Occasionally a tiny part is free (< 1%)

free fluid rivulets and vesicles

Capillary Exchange of Water The pathways for fluid movement across capillary walls are both

paracellular (clefts, fenestrae, gaps) and transcellular

(aquaporin1 water channels)

The main mechanism for fluid transfer across capillaries is

convection (bulk water movement) and depends on hydrostatic

and osmotic forces = Starling forces (1856)

Starling Forces1) The capillary hydrostatic pressure (Pc) forces fluid outside

the capillary

2) The interstitial fluid hydrostatic pressure (Pif) forces fluid

outside the interstitium when is positive and attracts fluid into

interstitium when is negative

3) The capillary plasma colloid osmotic pressure (Pp)

caused by plasma proteins, keeps water inside the

capillaries

4) The interstitial fluid colloid osmotic pressure (Pif)

caused by interstitial protein and proteoglycans, keeps water

into interstitium

The Net Filtration Pressure NFP, is the algebraic sum of

hydrostatic and colloid osmotic

forces acting across the capillary

wall

If the NFP is positive net fluid

outflow from the capillaries into

the interstitium = filtration

If the NFP is negative net fluid

absorption from the interstitial

spaces into the capillaries

DP DPArterial end

Capillary Filtration Coefficient The rate of fluid filtration in a tissue is also determined by the

number and size of the pores in each capillary as well as the

number of capillaries in which blood is flowing

the capacity of the capillary membranes to filter water for a given

NFP is expressed as the capillary filtration coefficient (Kf) or

hydraulic conductivity; unit measure: ml/min per mm Hg net

filtration pressure

The rate of capillary fluid filtration is therefore determined as

Filtration = the volume flow of fluid across the capillary wall

Capillary Hydrostatic Pressure In the human skin Pc falls from 30 mm Hg at the arteriolar end to

10 mm Hg at the venular end of the capillary

Pc depends on

Precapillary resistance (Rpre) and postcapillary resistance

(Rpost): usually Rpre > Rpost

midcapillary pressure is not the mean value between arteriolar and

venular pressures

Arteriolar and venular pressures: Rpre > Rpost Pc follows

venular pressure Pv more closely than arteriolar pressure Pa

Location: high Pc in the glomerular capillaries of the kidney, retinal

capillaries; low Pc in the pulmonary capillaries

Time: the permanent fluctuation of the arteriolar diameter and tone of

the precapillary sphincter lead to times of net filtration and other times

of net absorbtion in individual capillaries

Gravity: capillary beds bellow the level of the heart have a higher Pc

than those above the level of the heart

EFFECT OF UPSTREAM AND DOWNSTREAM PRESSURE

CHANGES ON CAPILLARY PRESSURE*

Pa (mm Hg) Pc (mm Hg) Pv (mm Hg)

Control 60 25 15

Increased arteriolar

pressure

70 27 15

Increased venular

pressure

60 33 25

*Constant Rpost/Rpre= 0.3.

Interstitial-Fluid Pressure Pif is sub-atmospheric (slightly negative) in loose tissues,

averaging about - 3 mm Hg

Pif is positive in encapsulated organs (kidney, muscle, eye etc.)

and inside rigid enclosed compartments (bone marrow, brain);

however, Pif in the parenchima is lower than pressures exerted

by their encasements (kidney: capsular pressure = +13 mm Hg,

Pif = + 6 mm Hg)

the normal interstitial fluid pressure is several mm Hg

negative with respect to the pressure that surrounds each

tissue (capsular pressure, barometric pressure)

The negative Pif is due to fluid removal by the lymphatic pump

Capillary Coloid Osmotic Pressure Molecules or ions that fail to pass through the pores of a

semipermeable membrane exert osmotic pressure; water is

attracted towards the compartment with a higher concentration of

osmotic-active particles (and lower “water concentration”)

Proteins of the plasma and interstitial fluids do not readily pass

through the capillary pores they are responsible for the

osmotic pressures on the two sides of the capillary membrane =

colloid osmotic or oncotic pressures

Pp averages about 28 mm Hg

19 mm of this is caused by molecular effects of the dissolved protein

and

9 mm by the Donnan effect - that is, extra osmotic pressure caused

by sodium, potassium, and the other cations held in the plasma by

the electro-negatively charged proteins

Types of Plasma Proteins and Pp Osmotic pressure is determined by the number of molecules

dissolved in a fluid small proteins develop a higher P

albumin is the most important protein for the capillary and

tissue fluid dynamics

Interstitial Fluid Colloid Osmotic

Pressure Small amounts of proteins do leak through the capillary wall into

the interstitium (100 – 200 g/day); most of them are removed by

the lymph (95 – 195 g/day); a tiny part is reabsorbed at the

venular end of the capillary (5 g/day)

Protein leakage varies greatly from tissue to tissue (higher in the

liver: 4 to 6 g/dl, or intestines: 3 to 4 g/dl); the average Pif is

about + 8 mm Hg

Pif increases along the axis of the capillary because

protein - free fluid is filtered at the arteriolar end of the

capillary, decreasing protein concentration in the interstitium

(lower Pif)

protein-free fluid is reabsorbed at the venular end from the

interstitium, increasing protein concentration in the interstitium

(higher Pif)

Fluid Filtration at the Arterial End

of the Capillary

Fluid Reabsorption at the Venular

End of the Capillary

Net Filtration Pressure Along a

Capillary

DP DP

Starling Equilibrium for Capillary

Exchange

The amount of fluid filtering outward from the arterial ends of

capillaries equals almost exactly the fluid returned to the

circulation by absorption

The slight excess of filtration is called net filtration and it is the

fluid that must be returned to the circulation through the

lymphatics (2 ml/min for the entire body)

Interstitial Edema Edema (from the Greek oidema, for "swelling") is characterized

by an excess of salt and water in the extracellular space,

particularly in the interstitium

Occurs due to alteration in

Hydrostatic forces (high Pc due to immobile upright position,

varicose veins, pulmonary hypertension, right heart inssuficiency etc.)

Coloid osmotic forces (low plasma protein in nephrotic syndrome,

pregnancy, protein malnutrition, liver disease etc.)

Properties of the capillary wall (increased permeability due to

inflammation, breakdown of the tight endothelial barrier of the

cerebral vessels, ischemia – reperfusion etc.)

Lymphatic drainage (removal of lymph nodes for cancer surgery,

lymph nodes obstructed by malignancy, external compression of

limph vessels etc.)

Regulation of the Microcirculation Each tissue controls its own local blood flow in proportion to its

metabolic needs

Tissue metabolites regulate local blood flow in specific vascular

beds independently of the systemic circulation regulation

Can be:

Short-termed (acute control)

rapid changes in local vasodilation or vasoconstriction of

the arterioles, metarterioles, and precapillary sphincters

Long-termed

slow changes in flow over a period of days, weeks, months

increase or decrease in the physical sizes and numbers of

tissue blood vessels (angiogenesis)

Depends on local mechanisms mediated by

metabolic factors

endothelial factors

autoregulatory processes

The cardiac output is distributed among tissues in accordance to

their instantaneous needs the work of the heart is spared by an

optimized distribution of the blood flow

Acute Control

Blood Flow to Different Organs and Tissues Under Basal Conditions

During heavy exercise, muscle metabolic activity can increase more than 60-

fold and the blood flow as much as 20-fold (15,000 ml/min or 80

ml/min/100 g of muscle)

Role of Resistance in Precapillary

Vessels Modulating the contractility of VSMCs in precapillary vessels

is the main mechanism for adjusting capillary blood flow

Capillary flow is roughly inversely proportional to Rpre because

the aggregate Rcap is small, Rpost/Rpre ≈ 0.3 Rpre > Rcap+ Rpost

Rpre is the principal determinant of the overall resistance

of the microcirculatory bed (Rtotal)

Rpre is determined by smooth-muscle tone in arterioles, metarterioles, and pre-capillary sphincters (R = 8hl /pr4)

Metabolic Control There are two basic theories for the regulation of local blood flow

when either the rate of tissue metabolism changes or the

availability of oxygen changes:

Vasodilator theory

Oxygen and nutrients lack theory

Vasodilator Theory The greater the rate of metabolism, the greater the rate of

formation of vasodilator substances in the tissue cells

Chemical factors act directly on the VSMCs

LOCAL METABOLIC CHANGES THAT CAUSE

VASODILATION IN THE SYSTEMIC CIRCULATION

CHANGE MECHANISM

↓ PO2 ↓ [ATP]i, adenosine release

↑ PCO2 ↓ pHo

↓ pH ↓ pHo

↑ [lactic acid]o ↓ pHo

↓ [ATP]i Opens KATP channels

↑ [Adenosine]o Activates purinergic receptors

Adenosine

Formed by degradation of adenine nucleotides when ATP

consumption exceeds cell capacity to resynthesize high

energy phosphate compounds, due to

- increased local metabolism

- insufficient local blood flow

- fall in blood pO2

From tissue cells adenosine diffuses into VSMCs activates

adenosine receptors K channels open hyperpolarization

voltage-gated Ca++ channels close decreases [Ca2+]i

vasodilatation increased O2 supply

Oxygen Lack Theory In the absence of adequate oxygen and possibly of some other

nutrients (glucose, thiamine, niacin, riboflavin) blood vessels

simply relax and naturally dilate oxygen and nutrients supply

raises vasoconstriction periodic fluctuation of capillary

blood fow (vasomotion) regulated by the level of oxygen and

nutrients

Acute local feedback

control of blood flow

The vascular endothelium is the source of several important

vasoactive compounds

Vasodilators release – stimulated by shear-stress or in response to

acetylcholine

NO – acts through a cGMP – PKG pathway to decrease the

interaction between actin and myosin (decreases MLC

phosphorilation) as well as [Ca2+]i (SERCA activation)

EDHF – makes the membrane potential more negative

Vasoconstrictors release: endothelins (ETs) – long lasting and

potent effect; increases [Ca2+]i

Endothelial Factors

VASODILATORS VASOCONSTRICTORS

Nitric oxide (NO) Endothelin (ET)

Endothelium-derived

hyperpolarizing factor (EDHF)

Endothelium-derived

constricting factor-1 (EDCF1)

Prostacyclin (PGI2) Endothelium-derived

constricting factor-2 (EDCF2)

Autoregulation Despite large changes in arterial blood pressure the local blood

flow is maintained within a narrow range

In the physiological pressure range over which autoregulation

occurs (70 – 175 mm Hg), increases in pressure lead to

increases in resistance (flow is maintained approx. constant)

Autoregulation is an autonomous process

Realized through myogenic and metabolic mechanisms

Autoregulation Myogenic control: the stretch of VSMCs induced by increased

perfusion pressure triggers myogenic contraction (via membrane

stretch receptors and increased Ca++ inflow)

Metabolic control: the increase in PO2 (or decrease in PCO2, or

increase in pH) that follows an increase in perfusion pressure

triggers a metabolic vasoconstriction that brings the perfusion

pressure back to lower levels

Importance

With an increase in perfusion pressure, autoregulation avoids

a waste of perfusion in organs with an already sufficient flow

With a decrease in perfusion pressure, autoregulation

maintains capillary flow and capillary pressure

very important for organs sensible to ischemia (heart,

brain) or for organs that filter the blood (kidneys)

Long-Term Control In adults the size and shape of microcirculation remains rather

constant

Exceptions: wound healing, inflammation, tumor growth,

endometrial vessels during the menstrual cycle, physical training,

acclimatization to altitude

Sustained hypoxia is followed by the expansion of the vascular

bed by angiogenesis (= development of new vessels) and by

arteriogenesis (= development of collateral circulation)

PROMOTERS INHIBITORS

Vascular endothelial

growth factor (VEGF)

Endostatin

Fibroblast growth factors

(FGFs)

Angiostatin

Angiopoietin-1 (ANGPT1) Angiopoietin-2 (ANGPT2)

AGENTS THAT AFFECT VASCULAR GROWTH