Ocular circulattion

 1-Anatomy of the ocular circulation .
 2-Blood ocular barriers : anatomy & physiology .
 3-Techniques for measuring ocular blood flow.
 4-Ocular circulatory physiology.
 5-Ocular blood flow & its regulation in diseases
Objectives

 The ocular circulation is unique and complex because of
the presence of two distinct vascular systems, namely:
 Retinal and Uveal systems.
 The ocular vessels are all derived from the ophthalmic
artery , a branch of the internal carotid artery.
 Both differ morphologically and functionally from each
other.
 Part of this circulation , supplying the fundus of the eye
can be observed ophthalmoscopically .
Anatomy of ocular
circulation

 Arise from the medial aspect of the 5th bend of
internal carotid artery as it emerge from
cavernous sinus .
 Supply the orbit , globe , forhead and lateral
nasal wall .
 Providing anastamosis between ICA & ECT .
 Composed of 3 segments ( intracranial ,
intracanalicular , intraorbital )
 Intraorbital segment composed of 3 parts .
 Gives off several branches , starting with central
retinal a & main posterior ciliary a ( contributing
to ocular circulation ) and ending with two
terminal branches : dorsal nasal &
supratrochlear arteries .
Ophthalmic artery

 Arise from first segment of intra-orbital portion of ophthalmic
artery.
 0.3 mm in diameter.
 Pierce the Dural sheath of optic nerve about 12.5 mm (10-15mm)
behind the globe from its infero-medial side , it first pierce the
dura and arachnoid matter from both of which it obtains a
covering , on reaching subarachnoid space it bends forward ,
within a short distance it turn at right angle and pierce the pia
matter from which it also obtains a covering , on reaching the
center of the optic nerve it bends forward , toward optic n head .
 Loss its IEL and elastic tissue upon entering lamina cribrosa. GCA
 Adventitial covering contains both myelinated and unmyelinted ,
sympathetic and parasympathetic nerves.
Central retinal
artery

Arise from the ophthalmic artery while it crosses the
optic nerve as 2-3 main posterior ciliary arteries (lateral
and medial) branch into:
 Short posterior ciliary arteries
 Long posterior ciliary arteries
Posterior ciliary arteries

1-ophthalmic artery.
2-Central retina artery.
3-Lateral main posterior ciliary artery.

 10-20 in number which enter the globe at posterior
pole and assume a paraoptic and perimacular
patterns.
 Not accompanied by nerves in their course.
Paraoptic pattern:
 Smaller , fewer , piercing sclera closer to the optic
disc.
 Form an elliptical anastomotic circle through the
formation of superior and inferior perioptic optic
nerve arteriolar anastomosis.(circle of Haller and
Zinn).
 The circle incomplete in 23% of cases
 Complete with narrow sections 33%
 supply the peripapillary choroid, retrolaminar part
of optic nerve and to the pial arterial system
Short posterior ciliary
arteries

Branches of haller –zinn circle:
 Recurrent pial branches.
 Recurrent choroidal branches.
 Arteriolo-arteriolar anastomosis occur between pial
and choroidal branches.
The perimacular pattern:
 They are the majority and largest
 Pierce the sclera temporal to the optic nerve and
overlying the macula.
arteries

 The short posterior ciliary arteries lie in the
outer layer of the choroid (haller’s layer).
 Give rise on their deep surfaces to the choroidal
arterioles, which are in the intermediate layer
(Sattler's layer).
 At peripapillary border a few branches of the
choroidal arterioles cross the disc margin to
supply its prelaminar part.
 They supply the choroid from peripapillary
region till anterior to the equator.
arteries

 The two (nasal and temporal) long posterior ciliary arteries pierce
the sclera on each side of optic nerve outside circle of zinn-haller
and somewhat further anteriorly than short posterior ciliary
arteries.
 Each artery is accompanied by a ciliary nerve.
 Pass in oblique canal within the sclera about 4 mm in length
 They run forward within the suprachoroidal space in the
horizontal meridian
 Their course can be followed from outside by translucent blue line
& internally because of accentuation of pigment in the fundus
near their course.
 Recurrent branches supply the anterior choroid in horizontal
meridian.
 Bifurcate in the anterior choroid or sometimes within the ciliary
muscle , and after further divisions form the major arterial circle
of the iris , of which they are the predominant supplier .
Long posterior ciliary
arteries

 Derived from the muscular arteries to the four recti
muscles which pass within their substance.
 Two anterior ciliary arteries emerge from each
tendon at their insertion except that of the lateral
rectus muscle give rise single one.
 Perforate sclera at insertion of the recti muscles.
 run radially toward the limbus within the Tenon
capsule, about 1.5 mm from the limbus divide into
deep (scleral) and superficial anterior (episcleral).
Anterior ciliary arteries

 The deep scleral branches : dip almost directly to through
sclera to enter the ciliary muscle where they join the
intramuscular circle and gives off branches to the major
arterial circle of iris and recurrent choroidal arteries to
supply anterior choroid in vertical meridian mainly.
 Superficial episcleral branches :run in the episclera, near the
limbus they assume a circumferential course and
anastomose each other to form episcleral pericorneal
arterial circle.
 At the limbus , the episcleral arteries make a hairpin bend
and enter the bulbar conjunctiva as the anterior conjunctival
arteries
 The anterior conjunctival arteries anastomose with posterior
conjunctival arteries 4 mm from the limbus.
Anterior ciliary arteries

 From previous slides we conclude that:
 Anterior ciliary arteries supply the perilimbal
bulbar conjunctiva, the limbus , iris , ciliary muscle
and the episclera.
 In anterior uveitis , keratitis the ciliary system is
congested , dilatation of episcleral and limbal
vessels gives rise to a characteristic circumcorneal
(ciliary injection).
 Anterior segment ischemia may result from:
 Multiple disinsertion of recti muscles during squint
operation (three or more).
 Tight band in retinal detachment management .
which will press on long posterior ciliary arteries
and vorticose veins as well.
Conclusion

 The retinal circulation is an end arterial circle
without anastomosis.
 Arise from central retinal artery which enter the
globe through lamina cribrosa.
 Supply the inner 2/3 of the retina as far as the
inner nuclear layer.
 At the optic disc the central retinal artery divides
into two major superior and inferior branches .
These in turn divides into arterioles
 Each arteriole supply a quadrant of the retina ,
there is no overlap between quadrants and no
inter-arteriolar anastomosis in the same quadrant.
 These terminal arteriolar branches at almost right
angle to the main vessel.
Retinal circulation

 In approximately 25% of human eyes a cilioretinal
artery emerging from temporal margin of optic disc
arising from either short posterior ciliary artery or
from parapapillary choroidal artery to supply the
macular region , exceptionally feeding the foveal
region .
 The larger vessels lay in the retinal nerve fiber layer
closely adherent to internal limiting membrane and
there is close spatial relationship between the
astrocytes and retinal larger vessel walls important
for maintaining vessel integrity.
 At arterio-venous crossing sites , the deeper vessel
may indent the retina as far as the outer plexiform
layer.
 Retinal arterioles distributed throughout layers of
the retina reaching as far as the internal nuclear
layer.
Retinal circulation

Relationship between astrocytes & endothelial cells

 Retinal arterioles give rise to plexus of capillaries (5 micrometer in
diameter) , which will form two interconnecting capillary plexus.
 These capillaries are smaller and nonfenstrated as compared to
choriocapillaries.
 first capillary network located in nerve fiber layer and ganglionic cell
layer
 deeper capillary network located in internal nuclear layer.
 In the peripapillary area , an additional capillary network lies in the
superficial portion of nerve fiber layer in a radial distribution pattern .
Retinal circulation

 Retinal capillaries changes :
 Towards the periphery the deep capillary net
disappears, leaving a single layer of wide mesh
capillaries.
 At the fovea a small area (400-500Mm) is
avascular to allow light to reach the
photoreceptors without encountering them
(foveal avascular zone).
 At extreme periphery about 1.5 mm wide area is
avascular.
 Capillary free zone also surrounds the arterioles
dueto local high oxygen tension affecting
capillary remodeling during retinal vascular
maturation .
Retinal circulation

 Retinal arteries are unique from other arteries of same
size in that they lack the internal elastic lamina and have
unusually well developed smooth muscle cells oriented in
circular and longitudinal manner , surrounded by basal
lamina with an increasing amount of collagene toward the
adventitia .
 Retinal capillaries composed of continuous endothelial
cells with tight junction , interrupted intrmural layer of
pericytes and basal lamina.
 Pericyte to endothelium ratio 1:2 and sometimes 1:1.
 Owing to pericyte contractile property and hight
representation in retina led to play a role in regulation of
retinal blood flow.
 There is no precapillary sphincter .
Retinal circulation / fine
structure

 Cross section in the wall of inner
retinal artery .

 it is the most posterior part of the uveal tract
extending from optic nerve posteriorly to the
ora serrata anteriorly.
 Considered to be homologue to pia and
arachnoid matter of the brain.
 Thickness estimated about 100 Mm anteriorly
and about 220 Mm posteriorly, with greatest
thickness over the macula.
 it may be thinner in high myopia and congenital
and chronic glaucoma.
 The choroid is composed almost entirely of
vessels .
 three strata are identified:
1. the stromal layer
It contains vessels, nerves ,cells and connective
tissue.
Stromal cells include melanocytes ,fibrocytes,
macrophages ,plasma cells and mast cells.
Choroid

The vessels of the choroid have a rich autonomic innervation but not to
retinal vessels.
 Sympathetic adrenergic fibers from superior cervical sympathetic
ganglion which have a vasoconstrictor action supply the choroid as
well as the central retinal artery up to lamina cribrosa but no further
more. These nerves show immunoreactivity to NPY
 Parasympathetic innervation from two sources:
1. Facial nerve from pterygopalatine ganglion and the unmyelinated
parasympathetic rami of the retrobulbar plexus.
A dense nitrergic (N.O.) and VIPergic perivascular network
Additional intrinsic network of choroidal ganglionic cells in the
choroid stroma whose neurons are connected to each other and to
perivascular plexus . they are concentrated chiefly in temporal and
central regions , about 2000 cell/eye
2. Oculomotor nerve from the ciliary ganglion via the short ciliary
nerves.
 Other neuropeptides of parasympathetic system include: peptide
histidine isoleucine and pituitary adenylate cyclase polypeptide.
Choroid

 Blood supply from :
 The short posterior ciliary arteries supply the
choroid posterior to the equator and a variable
area anterior to it.
 The temporal long posterior ciliary artery supplies
a wedge shaped area starting from point where it
enter the choroid posterior to the equator and
extending forward.
 Recurrent branches from major arterial circle of
the iris from the long posterior ciliary arteries and
from the anterior ciliary arteries supply anterior
choroid and anastomose with short posterior
ciliary arteries.
Choroid

 Secondary and tertiary branches of the short
posterior ciliary arteries are subsequently divide
in the stroma to form major choroidal vessels.
 Those lying in the outer layer composed of large
vessel called Haller’s layer giving a medium
vessel called Sattler’s layer .
 Haller’s and Sattler’s layer composed of :
-Large arteries measuring 40-90 Mm
-Large veins measuring 20-100 Mm
 Arteriolar branches of short posterior ciliary
artery that’s directed toward macular region
have spiral-shaped configuration while those
branches to the non-macular area expands in a
typical chevron V-shaped configuration.
Choroid

 The arteries have a muscular tunica media and an adventitia
of fibrillary collagenous tissue containing thick elastic fibers.
 Capillaries of choriocapillary layer are large in caliber than
retinal one.
 The capillary walls are fenestrated, consist of endothelial
cells joined by maculae occludentes and gap junctions with
pericytes disposed only on the scleral face of capillaries and
incompletely investing them.
 Ratio of pericyte to endothelial cells is about 1:6.
 Fenestrations are 60-80 nm in diameter, and are covered by
a thin diaphragm of attenuated cytoplasm which thickens
centrally.
 Fenestra are abundantly and evenly distributed on interior
face of choriocapillaries especially in submacular area.
 The choriocapillaries stops at the ora serrata.
Choroid / fine stracture

 The functional and anatomical vascular unit of the
choroid is the lobule.
 Each lobule has a feeding central arteriole and
capillary bed and peripheral draining venule.
 In the sub macular and peripapillary regions the
wide bore choriocapillaries arranged in honey comb
pattern.
 Peripheral to disc (beyond 3 mm) And peripheral to
macula (beyond 2 mm) and excluding the region
between the disc and macula the choroid has a
regular lobulated pattern.
 At the posterior pole the lobules are well organized
as round or polygonal ,and exhibit triangular
,pentagonal or octagonal in shape.
 Anteriorly the lobules increase in size and become
less organized.
 At the periphery the lobules are radially elongated
in a palm-like organization.
 This variable lobular arrangement of varying size
being larger in equator 200Mm than those in
posterior pole and submacular area measuring
100Mm and 30-50Mm respectively.
Choroid

 The sub macular choroid is supplied by 8-16
precapillary arterioles . which show frequent inter-
arteriolar anastomoses.
 The precapillary arteriole-to-venule ratio is 3:1 at
submacular region while at the posterior pole is 1:2
to 1:5.
 Limited functional anastomoses between the
lobules , divide choroid into several functional
island and behave as end-arteries with watershed
region that’s vulnerable to hypoxia-ischemia.
 Each posterior ciliary artery has its separate
territory of supply.
 the main posterior nasal and temporal ciliary
arteries together with their branches supply the
nasal and temporal choroid respectively.
 The lateral branch supply about 2/3 of the choroid.
 Limited functional anastomosis between the two
zones result in vertical watershed area which
usually centered on optic disc.
 Horizontal watershed areas also exist between
branches of short posterior ciliary arteries.
Choroid

 Blood is discharges from the lobules of
choriocapillaries by collecting venules.
 At posterior pole , a venules is located at
periphery of the lobule on the same plane and
may drain adjacent lobules.
 These venous plexus become less dense away
from the macula and become straighter , loss
their tortous aspect that found at the macula
 Vessel of larger lumen drain these venous
pluxes and eventualy flow into the vortex veins.
Choroid

A) V shape configuration of the posterior short ciliary arteries.
B) Subfoveal choriocapillary lobule.
C) Vortical venous trunk seen through the dense net of the choriocapillaries
D)Net of vortex veins centripetally towards the ampulla.
Choroid

 These are usually four in number,(two superior and
two inferior).
 Pierce sclera obliquely (may branches here) on each
side of the superior and inferior rectus muscles about
6 mm behind the equator.
 The superior veins leave the eye further back than the
inferior veins, and the lateral veins are closer to the
vertical plane than the medial.
 Superior lateral vein is most posterior 8mm behind
equator
 Inferior lateral vein is most anterior (5.5mm behind
equator).
 In myopic patients they may leave the globe further
back close to optic n
 The stem of the veins undergo ampulliform dilatation
just before they enter the sclera.
 Segmental venous drainage with watershed areas ,
horizontally between disc and macula and vertically
through papillomacular area.
 They drain into superior and inferior ophthalmic veins.
Vorticose veins

 For optimal cell function , Cell Barriers separate functional
compartments, maintaining their homeostasis , and
control transport between them , these modulated by
extracellular stractures namely extracellular matrix and
glycocalyx
 Two major pathways control transport through blood
retinal barriers , namely:
- transcellular pathway(transcytosis)
- Paracellular pathway
 These two pathway of different characteristic ,determine
the preferance of small solutes for either pathways , this of
particular important in drug absorption allowing drugs of
lipidsolube to pass the membrane but still poorly absorbed
dueto efflux pumps of the barrier.
Transport through blood
retinal barriers

1-transcellular pathway(transcytosis)
Actively and passively transport of water, ions , non-
electrolytes, small nutrients and macromolecules in an energy
dependent manner.
Most proteins transported non-selectively within vesicles via
Vesiculo-Vacuolar transport.
Constitutive transcytosis is the process by which
macromolecules are transported through the interior of a cell ,
particularly Albumin which is important in regulating
transvascular oncotic pressure gradiant.
Fenstration of endothelial cell membrane confer high
permeability as it found in choriocapillaries and neovessels.
2- Paracellular pathway:
Tight junctions between adjacent endothelial cell confer firm
intercellular adhesion and regulate paracellular permeability
through intercellular cleft.
These tight junctions are main determinant of barrier
permeability, they are polymeric adhesion complexes with a
transmembrane component composed of occluding, claudins
and junction adhesion molecules, linked to a cytoplasmic
plaque , this plaque inturn anchored to th actin cytoskeleton.
Water , ions and small non charged solutes employ the
paracellular pathway in passive diffusion along elecrochemical
and osmotic gradiaents.
Transport through blood
retinal barriers

 Other structures that are important in modulating
transport system responsiveness include:
1-Glycocalyx :
it is a thick macromolecules outer coating of plasma
membrane in the apical and luminal surfaces of
epithelial and endothelial cells consist of
(glycoproteins, proteoglycans, and
glycosaminoglycan), thus it is negatively charged.
Function:
It act as charge selective barrier that determines the
accessibility of certain molecules (cationic) to the
plasma membrane.
Help endothelium withstand blood flow stress.
Modulate the shear stress-induced release of NO.
Various enzymes ,growth factors , cytokines
associated with it.
Degenerative changes involving glycocalyx abolish
vasodilation response by NO.
Extracellular structures

2-Extracellular matrix:
Cell type-specific, the epithelium and vascular
endothelium both synthesize specialized ECM
scaffold, the basal lamina at their basal and
albuminal sides respectively.
Basal lamina serve as cell attachment sites by
means of variety of trans membrane receptors ,
best known among these receptors are integrins.
Disruption of integrin-matrix binding causes the
detachment of cells from their substrate and
increase in the permeability of tight junctions.
Physical, oxidative stress and inflammatory events
may affect the permeability of intercellular
junctions.
Extracellular structures

 Capillaries in the body are of 3 types :
 1- Continuous : endothelial cells adhere by tight junction ,
present in brain , retina and skeletal muscle .
 2- Fenestrated : numerous pores covered by thin membrane
, present in kidney , glands , ciliary body and choroid.
 3- discontinuous : numerous gaps allowing large cells to pass
, present in liver , spleen and bone marrow.
 The eye contain continuous and fenestrated types but none
of discontinous
 Variable range of permeability even in continuous type
owing to complexity difference of tight junction (
brain&retina show permeability less than 1% that of skeletal
muscle).
blood-ocular barriers

 Formed by tight junctions between endothelial cells lining the
retinal vessels, with absence of fenestrations and Relative
paucity of caveolae participate in tightness of the iBRB.
 Contains numerous transport systems like sodium-independent
GLUT1 for glucose.
 Both pericytes and smooth muscles prove structural support to
the vessel walls . Pericytes present in high density in retinal
blood vessel walls compared to other organs and play
important role in regulation of retinal perfusion.
 Pericytes play a major role in autoregulation by contraction
and relaxation , evidence for contractility:
1-Expression of a number of contractile proteins as Alpha-
smooth muscle actin, desmin , and non-muscle myosin.
2-Express receptors for vasoactive substances.
3-Absence of change in diameter in pericyte free vessels.
 Pericytes modulate barrier permeability since They express a
high number of caveolae that appear to be involved in
transcellular transport.
 Participation in secretion of basal lamina components so
involved in permeability property.
Inner blood-retinal
barrier

 In the retina both astrocytes and Müller cells
participate in vessel ensheathment.
 Glial cell important for vessel integrity and barrier
properties, via direct contact and release of
humeral factors, as:
 1-GDNF enhance barrier tightness.
 2-TGF-Beta decrease barriers tightness.
 3-VEGF directly downregulates tight junctional
proteins , so decreae trans-endothelial resistance.
 Other factors like TNF-alpha , interleukin 6.
Inner blood retinal
barrier

 Composed of three structural entities:
1- Fenestrated endothelium
The fenestration of choriocapillaries are covered by a
thin membrane with a central thickening , they have
high permeability with pore diameter of 4 A.
This will maintain adequate amount of glucose and
other nutrients at RPE level for Vit A cycle.
2-Retinal pigment epithelium:
RPE cells are equipped with transcellular pathway
system and an apico-lateral seal formed by
intercellular tight junctions, adherens junctions and
gap junctions, and in some species desmosomes.
The RPE is a relative tight epithelium with
paracellular resistance 10 times higher than
transcellular resistance.
Bidirectional transport : Nutrients , vitamin A are
transported from blood to photoreceptors and
transcellular transport from subretinal space towards
choriocapillaries important for removal of
metabolites, water and ions.
Outer blood-retinal
barrier

3-Bruch’s membrane:
Acellular lamina ,Provides tensile strength , Consist of five layers. 2Mm
Reservoir for growth factors thanks to the presence of proteoglycans.
It has overall negative charge due to the presence glycoconjugates, so
it is responsible for charge- selective restriction to the passage of ions
and solutes.
Its thickness increase with advancing age. Outer blood retinal
barrier
PR=photoreceptors external segment
PH=phagosome
BM=bruch’s membrane
RPE=retinal pigment epithelium
EC=endothelial cell
There is a defect in the barrier exist at optic n. head as a result of
continuity between extravascular space of choroid and prelaminar
region of optic nerve (pars choroidalis) but furthure diffusion to
peripapillary retina is prevented by tight junction between
astrocytes forming :
- Intermediary tissue of kuhnt
- Central tissue meniscus of kuhnt

 It control the secretion and transport of aqueous
humor to PC.
 Posses active and passive transport mechanisms.
 Anterior Blood-aqueous barrier consist of the tight
junctions between endothelium of iris capillaries, the
iris pigmentary epithelium , allows transcellular
transport by vesicles while paracellular transport is
controlled by presence tight junctions according to
concentration gradients , it represent an obstacle to
the passage of activated T-cell.
Anterior surface of the iris contain one layer of
fibroblast and not involved in BAB.
 Posterior Blood-aqueous barrier consists of tight
junctions on the lateral pole of inner non-pigmented
ciliary epithelium .these tight junctions are permeable
to small non ionic molecules like sucrose.
 The capillary endothelium of ciliary stroma possesses
fenestrations that makes its permeability relatively
high , while ciliary muscle capillaries appears relatively
tight similar to those of the iris.
Blood-aqueous barrier

Techniques used in experimental animals:
 1-cannulation of uveal veins .
determine arterio-venous difference in oxygen and glucose.
 2-Radioactively labeled microspheres.
the recovered particles / total no. of injected = fraction of
cardiac output to each organ
 3-calorimetry or thermocouple.
 4-study of oxygen partial pressure profile within the retina
with microelectrodes
 5-radioactive krypton desaturation
 6-hydrogen clearance
 7-glucose consumption by tissue uptake of labeled D-
glucose. ( not direct measure )
Techniques for measuring
ocular blood flow

Non-invasive techniques:
 1-retinal vessel analyzer
 2-digitized fluorescein angiogram.
 3-indocyanine green for study of choriocapillaries.
(with simultaneous use of OCT)
 4-bidirectional laser Doppler velocimetry.
 5-laser Doppler flowmetry.
 6-Laser speckle flowgraphy.
 7-Blue field stimulation technique.
Techniques for measuring
ocular blood flow

It allow continuous recording of diameter
change evoked by various physiological
maneuvers. ( dynamic measurement )
Diagram shows The diameter ,D, of a
retinal vessel segment
P1-P2 and variation of diameter with time
the subject was given 100% oxygen to
breathe
Retinal vessel analyzer

 Obtains dilution curves to measure the mean
circulation transit time (MTT, or MCT)
 Specific conditions must be standarized to
obtain precise MCT/MTT as in DRP dueto
fluorescein diffusion we gain approximate
MCT/MTT
 Other parameters : mean velocity of dye (MVD)
and arteriovenous passage time (AVP) not reflect
the flow of fluorescin.
 Diagram of retinal vascular segment extending from artery to a vein
with baths of different lengths. S point is the site of injection of
fluorescein, A point is the site of measurement of the fluorescein
along the artery, B point is the site of measurement of fluorescein
along the vein.
Digitized fluorescein angiogram

 Better than fluorescein in studying
choroidal circulation because :
 Fluorescence of ICG near IR and not
blocked by pigmented epithelium
 ICG almost completely protein bound and
does not leak through choriocapillaries
 Used to examine subretinal neovascular
membrane .
 OCT & ICG fluorescence:
New approach to study choroidal BF.
Indocyanine green
(ICG) angiography

 A)the Doppler effect.
 B)principle of BLDV .
 laser light scattered from blood in a
retinal vessel is detected along two
directions
 Bidirectional laser Doppler velocimetry
allow the measurement of absolute
velocity of blood . Retinal blood flow is
calculated from centerline velocity
(Vmax) of red blood cells combined with
Diameter measurements of these
vessels:
 BFmean= pie*D^2/4 * Vmean
 Vmean =Vmax/2
 Vmax increase linearly with D.

 Measurement of the change in flux of RBC in the vessels
which is proportional to BF when hematocrit is constant.
 Either dynamic or scanning mode , the former occur in
continuous way at discrete site while the latter provide
2D image of flux in the capillaries of optic disc and
peripapillary retina.
 In any of laser-based techniques , measured flux depends
on scattering and optical absorption properties of the
tissue , so comparision between flux value from different
eyes may not valid .
laser Doppler flowmetry (LDF)
Blue field stimulation technique
 The velocity and number of leckocytes moving in retinal capillaries of the macular region .
 Based on entoptic perception of one’s own leukocytes.
 VA must be better than 20/50

A)Tissue scattering model of Bonner and Nossal,provide the Basis of laser Doppler velocimetry. Scattered light by moving RBCs and non-moving tissue compnents.
B)Intensity and perfusion images of the optic nerve and peripapillary temporal retina obtained by laser Doppler flowmetry.

 Blood flow through a blood vessel depends on perfusion
pressure (PP) and the resistance of blood vessel wall (R).
 Perfusion pressure is the pressure that drives the blood
through the vessel.
 Hagen-Poiseuille law: for an incompressible uniform
viscous liquid (n) flowing through a cylindrical tube(length
L) with radius (r)
 BF=PP/R R= viscosity* L/2 pie r^4
 The mean ocular perfusion pressure driving blood through
the eye is the mean blood pressure in ophthalmic artery
minus the pressure in the veins that leave the eye . the
venous pressure is close to IOP.
 With subject in standing or sitting position the mean
ocular perfusion pressure (PP) is about 2/3 of the mean
brachial artery blood pressure (ABP).
 PP=2/3[ABPdiast+1/3( ABPsys – ABPdiast )]- IOP
 Change in blood viscosity ( high PCV , leukemia, sickle cell
dz ) alters speed of blood flow , may induce stasis in
venous blood and ultimately their occlusion.
 The main resistance o ocular blood flow is located in the
arterioles , R is proportional to 1/r^4
General hemodynamic
consideration

 Retina
Retinal blood flow represent only 4% of total ocular blood
flow. In primates 25-50ml/min/100g.
In human , Retinal blood flow 40.8-52.9 Ml/min.
Retinal blood flow is larger in the temporal region than
nasal , supposedly due to the larger size (by20-25%) blood
vessels and higher metabolic rate .
Retinal blood flow in superior and inferior hemispheres are
similar. Also applied for the macula.
 Choroid
In animals choroidal blood flow is estimated about 500-
2000 ml/min/100 g tissue but there is no technique allowing
reasonable measurement of choroidal blood flow in
humans.
The importance of high choroidal blood flow would tend to
maintain ocular temperature near body temperature during
environmental cooling or heating , protect the from thermal
damage induced by light of high intensity as in fovea and
efficient delivery of oxygen and glucose to the retina in
about 65% , 75% respectively
Ocular hemodynamic
data under normal
physiological
conditions
The arterio-venous difference of oxygen content in choroidal blood 3% ,
While that of retinal blood is about 38% lower oxygen in veins than arteries

 Ciliary circulation:
Direct estimation of ciliary blood pressure have not been
made, but reasonable estimate outside the eye is 67mmHg
for human in upright position with arterial BP 100mmHg.
Episcleral blood pressure is approximately 9mmHg which is
reasonable approximation of the pressure in vortex v.
The venous pressure inside the eye is determined by IOP. (1-2
mmHg higher than IOP)
Capillary pressure is also IOP dependent and equals 8 mmHg
higher than IOP.
Plasma clearance of ascorbate provide rough estimate of
ciliary plasma flow of 73Ml/min or a ciliary blood flow of
133Ml/min in human eye assuming normal hematocrit.
Ocular hemodynamic
data under normal
physiological
conditions

 Vasomotion
There are no precapillary sphincters and BF appears to be
uninterrupted in all capillaries.
Temporal fluctuations of ONH and subfoveal choroidal
blood flow , with frequencies >10 cycles/ min and distinct
peak at the breathing and heart beat frequencies.
 Effect of age on ocular blood flow:
Diameter of main retinal arterioles and venules depend on
age and pressure.
it is narrower in older than younger people.Diameter
decrease about 2Mm for each decade of increasing age.
Arteriolar diameter is narrower in subjects with higher ABP.
Aging leads to a decrease in blood volume, RBC velocity , and
velocity and number of leukocytes in macular area due
presumably to the age related morphologic decrease of
retinal cells and nerve fibers.
Age dependent decrease in subfoveal choroidal blood flow
due to reduction in the diameter and number of
choriocapillaries .
Ocular hemodynamic
data under normal
physiological
conditions

 It is complex due to presence of two different
vascular systems.
 The retinal and ONH vessels have no neuronal
innervation and relay on local control while
choroidal vessels autonomically innervated.
 The mechanisms controlling ocular blood flow
are systemic, local, neural, endothelial,
endocrine and paracrine.
 Retinal and choroidal arterioles do not posses
sphincters so blood flow is the function of the
muscular tonus of the arterioles and pericytes
contraction.
 Vessel tonus is modulated by multiple control
mechanisms : myogenic , metabolic , neurogenic
and humoral factors by vascular endothelium or
glial cells surrounding the vessel.
Regulation of ocular
blood flow

It is the intrinsic ability of the tissue to maintain relatively constant
blood flow despite variations in perfusion pressure.
Retina and optic nerve head:
 Retina lack sympathetic innervation and protected from circulating
hormones by tight BRB.
 Mechanism underlying autoregulation has myogenic and metabolic
components.
 A moderate reduction in PP in human eye induce an autoregulatory
response(increase diameter D of arteries and maintenance of
constant retinal and ONH blood flow if PP is not reduced more than
50%).
 Auto regulatory mechanism evoked by Increase PP above normal
induced by decrease IOP below normal.
 oxygen tension in inner retina and ONH not affected by Moderate
increase in the IOP.
 When PP is actually reduced (>50%) by increasing IOP, vasodilation
induced by increase lactate concentration by retinal metabolism ,
rapid response within seconds.
 Recent evidence of a major role of NO in ONH autoregulation.
Autoregulation of
ocular blood flow

 Choroid
 Measurements of subfoveal choroidal blood flow with
LDF reveal non linear decrease of blood flow in response
to decrease in PP. suggests some autoregulatory
mechanism mediated by dense vasodilatory innervation
of choroid localized in temporal-central part close to
fovea.
 Anterior uvea:
 Iris blood flow shows no evidence of autoregulation in
humans , but present in animal detected by labeled
microspheres.
Autoregulation
of ocular blood flow

 Static exercise:
 Isometric exercise increase heart rate , ABP and
sympathetic tone.
 Retinal ,subfoveal choroidal and ONH remain
unchanged until the mean ocular pressure is
elevated y average of 34-60% above baseline.
 The regulation achieved partly by local increase in
vascular resistance , as evident by constriction of
retinal arterioles since there is no innervation.
 In the choroid the sympathetic nervous system
constrict the vessels
 ET-1 and NO play important role in regulation of
subfoveal and choroidal BF during isometrics.
Regulation of blood
flow in response to
increase in arterial
blood pressure (ABP)

 Dynamic exercise:
 In response to it the IOP decrease the ABP increase
, but peripheral and macular retina and choroidal
blood flow remains unaffected.
 A sympathetic mechanism protecting choroid from
overperfusion has been postulated.
 Change in posture:
 The change from upright or sitting to supine
position induce a 16% decrease in heart rate and
increase in IOP.
 The ophthalmic artery pressure is higher in supine
position, this will stimulate decrease retinal vessel
diameter D.
 Peripheral and macular BF remain unaffected so it
is autoregulated.
 Recumbency increases subfoveal choroidal BF
about 11% , this linear relatioship indicate passive
response with lacking autoregulation.
Regulation of blood
flow in response to
increase in arterial
blood pressure

Hyperoxia
 Marked vasoconstriction of retinal arterioles , and marked
decrease in retinal blood flow in reponse to high PaO2.
 Retinal BF response is 3-4 times greater than that of cerebral
circulation.
 Choroidal blood flow doesn’t change considerably.
 ET-1 contributes to hyperoxia induced retinal
vasoconstriction.
 Selective ET-1 antagonist BQ-123 blunt this response .
 The retinal PO2 response to hypoxia is species dependent.
Hypoxia:
 Decrease in PaO2 induce in the retina vasodilation of the
arterioles and increase in blood flow.
 This is mediated by increase in lactate which will stimulate
endothelium release of NO.
 PO2 remain constant when PaO2 is above 40 mmHg.
 Choroidal vessels show passive response with linear
reduction.
blood flow in
response to change
in blood gases

Hypercapnia:
 Ocular BV is very sensitive to variation in PaCO2 , for 1
mmHg rise in PaCO2 =3% rise in retinal BF.
 Hypercapnia shorten MCT, dilate retinal vessels, macular
leukocyte velocity, RBC velocity . Choroidal BF increases
 Increase in retinal blood flow by mechanism involving NO
synthase NOS-1 and release of PGE2 mediated endothelial
NO.
 Endothelial interaction between PG and NO control
arteriolar tone during hypercapnia .
 IV indomethacine (inhibitor of PG synthetase) decrease
retinal BF by 20% without effect on uveal BF.
 IV acetazolamide cause metabolic acidosis with increase in
PaCO2 cause increase in retinal and ONH BF.
 Carbogen is a gas mixture (5% CO2+95% O2) increase
retinal BF without causing vasoconstriction as pure O2
It is of doubtful use in fully developed RVO , some
improvement in selected cases of pre-occlusion RV
blood flow in
response to change
in blood gases

Interaction between Substances released either from
endothelial cells, glial cells or neurons affect the
arteriolar tone.
Tone relaxing include:
NO ,prostacyclin(PGI2) ,VIP, adenosine , pituitary
adenylate cyclase activating polypeptide , dopamine
(D1 and D5) , drugs like: acetylcholine ,papaverine ,
aminophylline , pilocarpine
Tone contracting include:
Endothelin-1 (ET-1), angiotensin2, cyclo-oxygenase
products (COX) such as thromboxane A2(TXA2)and
prostaglandin H2( PGH2).
Lactate-induced retinal arteriolar dilatation via NO
synthetase and subsequent activation of guanylyl
cyclase.
Unknown substace mediate retinal arterial
vasodilation via activation of membrane Ca-ATPase.
Metabolic control of
retinal blood flow

 Retina had high rate of glycolysis with 90%
glucose converted to lactate and 70% of O2
used for oxidation of glucose to CO2.
 Lactate produced aerobically and
anaerobically(2-3fold higher) even in high
starting lactate concentration.
 Lactate has Dual vasoactive capability:
- rise Ca in pericytes lead to contraction of
microvessels
- vasodilation in hypoxia via endothlia release
of NO.
This response occur according to local metabolic
needs.
Retinal metabolism and
vasoreactivity

Light/dark transition:
 Retinal vessels Blood flow increases after transition from
dark to ambient light by observing increase in retinal
vessel D from 2-3% to 5-8% and blood velocity by LDV
with an increment 40-70%.
 Increase in retinal metabolism occur during darkness.
 Subfoveal choroidal BF decrease by 15% after transition
from light to dark even when only one eye is subjected
to the transition suggesting central mechanism
mediated via NO form endothelia and neural source.
Luminance Flicker:
(illumination with alternating brightness)
 Increase glucose uptake in ganglionic cell layer.
 Increase retinal vessel D as well as retinal and ONH BF
Hyperemic response.
 Function of this response : increase retinal glucose
metabolism, increase delivery of glucose and oxygen ,
NO production.
 Reduction in this response occur in DM , glaucoma and
untreated arterial HT.
Blood flow response
to visual stimulation

 Flickering of light increase glucose uptake by
Ganglion cell layer (red line) compared to glucose
Uptake in darkness.

 Flicker induced change of
diameter of retinal vessel
measured by RVA in 5 subjects ,
stimulus started at 0 time and
lasted 20 sec .

 Mean time course of changes (in pecent)in
velocity and flux of red blood cells measured
at a temporal site of the human optic disc in
response to a diffuse luminance flicker

 Nitric oxide produced via NO synthetase , 3 isoform of NOS
 NOS-1 neuronal, NOS-3 endothelial, both Ca-calmodulin
dependent while NOS-2 Ca-indepandant production in
inflammatory and immunological stimuli
 NOS-1 in retina is present in ganglion, amacrine, horizontal,
photoreceptors and muller cells , while NOS-3 in retinal and
choroidal vascular endothelia and pericytes of particular
important in ocular BF
 Analogs of L-arginine (L-NMMA,L-NAME) is a competitive
inhibitor of all 3 isoform of NOS thus NO production , its use
indicate NO produced under physiological conditions .
 NO ivolved in variety of agonist induce vasodilatation :
histamine, insulin, hypercapnia, adrenomedullin .
 NO play a role in flicker induced hyperemic reponse of ONH
Control of arterial tone
by endothelium or
neuro-glial activity

 Endothlins prsent in 3 isoforms ET-1,2,3 in vascular endothelium.
 ET-1 also present in retinal neurons, astrocytes and brain, most
potent VC
 Tow types of ET receptors: ETa , ETb ,the former express high
affinity for ET-1
 ETb recptors of two subtypes, ETb1 mediate vasorelaxation via NO
release , reduce ET-1 level and thus ETa activation while ETb2 high
affinity for ET-3 and mediate vasoconstriction
 Dual block of ET a+b receptors increase retinal BF
 Analogue of L-arginine blocking NO producing unopposed action of
ET.
 Prostaglandins
 Pericytes of retinal capillaries release PGE2,PGF2a,PGI2
 PGE2 + PGF2a are predominant PGs released by retina and choroid
 PGs modulate glial response via : glial-evoked dilation (EET) and
glial-evoked constriction (HETE)
 PGF2a has vasodilation and increase permiability to albumin while
slective postanoid FP receptor agonist lack
Control of arterial tone
by endothelium or
neuro-glial activity

Vasoactive nerves:
 Sympathetic stimulation :
 Reduce choroidal blood flow . mediated by alpha 1 receptors and non-
adrenergic neuropeptide Y. It is blocked by alpha adrenoreceptor
blockade but this unmask sympathetic mediating vasodilation via
Beta1 receptor-NO release by endothelium
 NPY in humans is release only at high level of stress thus the role in
normal unclear
 Parasympathetic stimulation:
 Causes choroidal vasodilation and Increase choroidal blood flow,
mediated by acetylcholine , pituitary adenylate cyclase activating
polypeptide, VIP and NO.
 Blocked by ganglion blockade suggesting nicotinic synapse between
CNS and eye
Adenosine: induce retinal vasodilation via adenosineA2 receptor , play a
role in hypoxia-induced vasodilation and retinal autoregulation, it also
increase choroidal and ONH BF flicker induced hyperemic response .
Neural , endocrine and
Paracrine control of
ocular blood flow

 Depends on the route of administration and the tissue , most
of topical route expected to act on anterior uvea with little or
no in Posterior segment , concentration in <10%
 Close arterial injection may give benefit or worsen BF as in
systemic VD
 Most of systemic drugs are prevented from reaching retinal
smooth muscle by BRB except for papaverine which is lipid
soluble Intravetrial injection to bypass BRB
 Vasoconstrictors : topical epinephrine and brimonidine
decrease BF in anterior uvea , systemic norepinephrine has no
effect on retina BV but affect choroidal BF with sig. rise ABP
 Vasodilators : topical pilocarpine, CAI, PGf2a analogue act on
anterior uvea only
systemic CAI increase retinal oxygen tension close to ONH via
hypercapnia
 Dopamine system produce complex response
Dopamine antagonist increase ocular BF , dopamine itself induce
vasodilation in choroid via D1/D5 receptors and vasoconstriction
via D2,3,4 receptors.
Endogenous and
pharmacological
substance in controlling
ocular BF

Diabetes
 Increase in D of retinal arterioles and venules in early dz
 Retinal BF unaffected in eyes with well controlled DM , reduction in
BF occur in later pDRP with sever capillary non-perfusion
 Reduced vasoconstrictive response to hyperoxia related to retinal
edema
 Reduction in adjusting retinal BF in reponse to change in PP as in
increase in IOP and isometric exercise especially in autonomic
dysfunction
 Blunted retinal v D response to flicker due to endothelial dysfunction
or decrease in neural activity 2nd to muller glial cell abnormality
 Reduced subfoveal choroidal BF in patient with DM dueto macular
edema
Ocular BF and it’s
regulation in diseases

Glaucoma
 Reduction in ONH BF in glaucoma pt may be
dueto neuronal loss or causative factor
 Impairment in retinal autoregulation in pt with
glaucoma via blue field test shows
autoregulation max IOP level : 25+/-1.5 mmHg
POAG while 30+/-3.6 mmHg in normal subjects.
 Autoregulation is intact in ocular HT as the
change return to normal after therapeutic
lowering IOP
 ONH respnse to flicker is significantely
diminished indicating neural impairement
 Impairment of ONH BF autoregulation in pt with
ocular HT is a risk factor for development and
progression of glaucoma.

Age-related macular degeneration
 Thickening and loss of elastic tissue of ocular BV
due to atherosclerotic porcess and eventualy
reduction in choroidal BF.
 Vascular element involving AMD is supported by
lower LDF flow rate in eyes of pt with AMD as
compared to healthy eyes.
 Relationship between AMD and reduction in
choroidal BF represent a risk factor for choroidal
neovasculartization.

Ocular circulattion

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