Vascular Reactivity of Optic Nerve Head and Retinal Blood Vessels in Glaucoma - A Review

Vascular Reactivity of Optic Nerve Head and RetinalBlood Vessels in Glaucoma—A Review

SUBHA T. VENKATARAMAN, JOHN G. FLANAGAN AND CHRIS HUDSON

Department of Ophthalmology and Vision Science, University of Toronto, Toronto, and School of Optometry, University of Waterloo, Waterloo,

Ontario, Canada

Address for correspondence: Professor Chris Hudson, Department of Ophthalmology and Vision Science, University of Toronto, ON M5T 2S8,

Canada. E-mail: [email protected]

Received 13 December 2009; accepted 2 May 2010.

ABSTRACT

Glaucoma is characterized by loss of retinal nerve fibers, structural

changes to the optic nerve, and an associated change in visual

function. The major risk factor for glaucoma is an increase in

intraocular pressure (IOP). However, it has been demonstrated

that a subset of glaucoma patients exhibit optic neuropathy

despite a normal range of IOP. It has been proposed that primary

open angle glaucoma could be associated with structural

abnormalities and ⁄ or functional dysregulation of the vasculature

supplying the optic nerve and surrounding retinal tissue. Under

normal conditions, blood flow is autoregulated, i.e., maintained at

a relatively constant level, in the retina and ONH, irrespective of

variation in ocular perfusion pressure. A number of factors

released by the vascular endothelium, including endothelin-1 and

nitric oxide, are suggested to play an important role in the

regulation of local perfusion in the retina and ONH. Most work

to-date has investigated homeostatic hemodynamic parameters in

glaucoma, rather than the measurement of the hemodynamic

response to a provocation. Future work should comprehensively

assess blood flow in all the ocular vascular beds and blood vessels

supplying the eye in response to standardized stimuli in order to

better understand the pathophysiology of glaucomatous optic

neuropathy.

Key words: Glaucoma, retina, optic nerve head, vascular reactivity

Abbreviations: ACE, angiotensin-converting enzyme; ANS,

autonomic nervous system; AT, angiotensin; cAMP, cyclic

adenosine monophosphate; CDI, color Doppler imaging; cGMP,

cyclic guanosine monophosphate; CNS, central nervous system;

CO2, carbon dioxide; CRA, central retinal artery; EDCF,

endothelium-derived constricting factors; EDRF, endothelium-

derived relaxing factors; eNOS, endothelial nitric oxide synthase;

ET-1, endothelin 1; FPA, fundus pulsation amplitude; GON,

glaucomatous optic neuropathy; HRF, Heidelberg retina

flowmeter; IOP, intraocular pressure; LC, lamina cribrosa; NO,

nitric oxide; nNOS, neuronal nitric oxide synthase; NTG, normal

tension glaucoma; NVG, neovascular glaucoma; OA, ophthalmic

artery; ONH, optic nerve head; OPP, ocular perfusion pressure;

PCAs, posterior ciliary arteries; PETCO2, partial pressure of

end-tidal CO2; PETO2, partial pressure of end-tidal oxygen; PG,

prostaglandin; POAG, primary open-angle glaucoma; POBF,

pulsatile ocular blood flowmeter; pPOAG, progressive POAG;

RVA, retina vessel analyzer; SLDF, scanning laser Doppler

flowmetry; SPCA, short posterior ciliary artery; (u)POAG,

untreated POAG.

Please cite this paper as: Venkataraman, Flanagan and Hudson (2010). Vascular Reactivity of Optic Nerve Head and Retinal Blood Vessels in Glaucoma—A

Review. Microcirculation 17(7), 568–581.

INTRODUCTION

Glaucoma is a condition that is characterized by a loss of

retinal nerve fibers, structural changes to the optic nerve,

and an associated change in visual function [46,99]. The

major risk factor for glaucoma is increased IOP [65]. The

most common treatment for patients with POAG focuses

on decreasing IOP. However, a subset of patients with

glaucoma exhibit IOP within normal limits, termed low

or normal tension glaucoma, but exhibit a similar optic

nerve neuropathy to patients with higher IOP. It has been

proposed that glaucoma, in particular NTG, could be

associated with structural abnormalities and ⁄ or functional

dysregulation of the vasculature supplying the optic nerve

and surrounding retinal tissue [25,66,162].

Recent studies have investigated homeostatic levels of

ONH and retinal blood flow [1,6,51,65,79,90,108,

119,179,210] and also the response of the retinal, choroidal,

ONH vasculature, and ⁄ or the OA to inspired gas stimuli

[85,90,188], light flicker [89,172], cold stress test [60,176],

and manipulation of OPP [136,157,203]. These studies

have provided some basic understanding of the possible

vascular abnormalities associated with GON. In turn, the

vascular abnormalities seen in POAG including NTG are

DOI:10.1111/j.1549-8719.2010.00045.x

Invited Review

568 ª 2010 John Wiley & Sons Ltd, Microcirculation, 17, 568–581

thought to be associated with an imbalance of certain vaso-

active factors, especially ET-1 and NO. ET-1 and NO are

primarily produced by the vascular endothelium and regu-

late blood flow by acting upon the surrounding smooth

muscle cells [14,66,72,133,153,158,207].

The primary aim of this study is to review recent litera-

ture on ONH and retinal blood flow and their response to

various provocations in patients with glaucoma. In addi-

tion, we also review the vascular endothelium-derived vaso-

active factors and their possible role in the pathogenesis of

POAG.

Pubmed–MEDLINE and Ingenta (Ophthalmic literature)

was used as the main source for literature search to obtain

a list of articles between the years 1995 and 2008. The fol-

lowing were the major search terminologies used: ‘‘blood

flow in glaucoma; vascular endothelial factors and glau-

coma; ET and NO in glaucoma; vasospasm and glaucoma.’’

Articles published in languages other than English were also

included during the literature search.

BLOOD SUPPLY OF THE RETINA AND THEONH IN HUMANS

The retina and the ONH are nourished by differing blood

supplies. The inner, or neural, retina receives its blood sup-

ply through the common carotid artery, internal carotid

artery, OA, and finally the CRA [28]. The outer retina, or

choroid, is nourished by the choriocapillaries via the com-

mon carotid artery, internal carotid artery, OA, and the

PCAs [209].

The ONH is stratified into four layers (Figure 1). The

superficial nerve fiber layer consists primarily of neurons

and is predominantly supplied by the inner retinal circula-

tion and in part by the SPCA in the temporal area [27,87].

The prelaminar region receives its blood supply from the

branches of the peripapillary choroid and from the SPCAs.

The third layer is the LC, which is principally supplied by

the SPCAs. The retrolaminar region lies outside the globe

posterior to the LC and is nourished by both the pial ves-

sels and the SPCAs [20,70,87,126].

HOMEOSTATIC BLOOD FLOW IN POAG

Recent developments in blood flow measurement techniques

have made the quantification of numerous hemodynamic

parameters possible [83]. However, the measurement of

blood flow in the eye is still very challenging partly because

of a poor signal-to-noise ratio. The design and the princi-

ple of the various blood flow measurement techniques used

to assess ocular hemodynamics in glaucoma have been

described in detail elsewhere [48,83]. The majority of previ-

ous research has suggested a decrease in blood flow in vari-

ous ocular tissue beds in patients with POAG or NTG.

A decrease in perfusion assessed by measuring the retinal

mean transit time has also been found that is similar in

both POAG and NTG [9].

PULSATILE OCULAR BLOOD FLOWMETERAND LASER INTERFEROMETRY

Using the POBF, Kerr et al. [108] reported decreased levels

of choroidal blood flow in (u)POAG compared to ocular

hypertension and controls. Other studies have also reported

similar findings in patients with POAG [1,50,100,107,184].

These results require careful interpretation as the POBF

does not measure blood flow directly. POBF measurements

are derived mathematically by estimating ocular pulse

volume change on the basis of a predetermined equation,

Figure 1. Diagram illustrating the blood supply to the optic nerve head. A, arachnoid; C, choroid; CRA, central retinal artery; Col Br., collateral

branches; CRV, central retinal vein; D, dura; LC, lamina cribrosa; OD, optic disk; ON, optic nerve; PCA, posterior ciliary artery; PR, prelaminar region;

R, retina; S, sclera; SAS, subarachnoid space. Reprinted by permission from: Progress in Retinal and Eye Research; 20: 563–593, copyright (2001).

Vascular Reactivity in Glaucoma—A Review

ª 2010 John Wiley & Sons Ltd, Microcirculation, 17, 568–581 569

which assumes a set value for ocular rigidity and relates

ocular volume to IOP. Assessment of choroidal hemo-

dynamics using FPA is in agreement with previous studies

showing a decrease in pulsation amplitude in POAG

[44,51,153].

SCANNING LASER DOPPLER FLOWMETRY

A decrease in blood flow in the ONH has been shown in

patients with POAG [11,44,51,79,107,131,141], NTG [119],

and glaucoma suspects [151]. Also, regional variation in

blood flow in healthy individuals was noted using the HRF

with the temporal neuroretinal rim of the ONH showing

reduced blood flow compared to the nasal area [10]. Evi-

dence of a positive correlation between blood flow in the

ONH and corresponding visual field defects has been dem-

onstrated in patients with NTG [179]. In addition, an

inverse correlation of blood flow to diurnal variation in

IOP in (u)POAG has been demonstrated [186]. These find-

ings might indicate a possible vascular abnormality in

POAG and NTG; however, none of the above studies have

determined retinal or ONH vascular reactivity in response

to provocations.

The assessment of retinal and ONH vascular regulation

provides additional information about ocular physiology

and can be disturbed in the absence of disturbance of

homeostatic retinal blood flow. Also, there is lack of a

comprehensive assessment of ocular vascular hemodynam-

ics in all the studies. Inner retinal blood flow might be nor-

mal in the presence of disturbed outer retinal blood flow,

or vice versa. More importantly, most of the studies share

the same limitation of using a surrogate parameter to indi-

cate differences in blood flow, rather than measuring blood

flow per se.

COLOR DOPPLER IMAGING

A decrease in retrobulbar hemodynamics in the OA and ⁄or CRA in POAG [8,11,19,52,105,152] and NTG

[18,54,85,91,105] has been shown. However, in patients

with nonprogressive POAG [210] and NTG [206], no

difference was found in retrobulbar blood velocity com-

pared to controls. The results of CDI-based studies require

careful interpretation in the respect that the technique is

unable to measure blood vessel diameter; it only measures

blood velocity that is assumed to indirectly denote blood

flow in the tissue of interest. Proper positioning of the

probe on the eye is critical as the resulting blood velocity

value depends on the angle between the incident beam and

the direction of blood flow.

Another confounding factor that has been overlooked

by the majority of the CDI-based and other studies is

that homeostatic blood flow was assessed in treated

POAG and ⁄ or in patients who had only recently stopped

IOP lowering medication without an adequate washout

period. The vascular effects of IOP lowering medications

remain controversial. One study has shown no effect of

IOP lowering medications on ocular blood flow [139],

whereas other studies report change in ocular blood flow

as a result treatment [31,116,127,132,187]. The average

wash-out period for these medications is four weeks, in

order to return to original IOP levels [31,191]. There is

lack of information on the recovery of any secondary vas-

cular effects induced by these drugs [108]. The presence

of any residual vascular effects can thereby mask or exag-

gerate a true difference in measured baseline blood flow

results.

REGULATION OF OCULAR BLOOD FLOW

The eye is supplied with autonomic nerves within the uvea

and the PCAs [2,49]. The retina lacks autonomic innerva-

tion and blood flow is regulated as a result of a myogenic-

driven negative feedback mechanism and by local tissue

demands. In most tissues, arterioles are thought to be the

major site for the regulation of perfusion [87,144,158].

However, there is also increasing evidence that the pericytes

in retinal capillaries might also regulate perfusion at a local

level [3,4,120,149,158].

Autoregulation is defined as the ability of a tissue to

maintain blood flow at a constant level despite changes in

perfusion pressure. Guyton et al. [71] expanded the origi-

nal definition of autoregulation to include tissue responses

to changes in blood gas levels, sometimes referred to a

metabolic autoregulation. The change in hemodynamic

parameters in response to provocations such as CO2

[37,81,108,199], oxygen [32,62,109,195], cold stress

[88,135,140,161,176], or light flicker [42,89,155,170,172] is

often referred to as vascular reactivity, particularly in the

cerebral blood flow literature.

Regulation of blood flow in the eye is achieved through

metabolic, myogenic, neural, and hormonal mechanisms.

Metabolic autoregulation is the regulation of the retinal

and ONH vasculature by the local concentration of oxygen,

CO2, potassium, or hydrogen [82,87,144]. Increased con-

centration of blood lactate results in increased retinal blood

flow and also a trend to increase choroidal blood flow

[59]. The exact mechanism involved has not yet been iden-

tified but it is proposed that cytosolic-free NADH fuels

a signaling pathway that releases NO, thereby increasing

the blood flow [94]. In another study, intravenous sodium

lactate reduced flicker-induced vasodilatation in retinal

arterioles assessed using the RVA but did not alter the

vascular response to exercise-induced increase of lactate

concentration [57]. The mechanism of metabolic autoregu-

lation is not well established but certain endothelial derived

S.T. Venkataraman et al.


relaxing and constricting factors are thought to play an

important role [24,32,38,46,47,82,134,154,158].

An increase in blood pressure leads to vasoconstriction

of arterioles, and vice versa, and thereby maintains blood

flow and this is termed myogenic autoregulation. It occurs

secondary to the activation of stretch-activated ion chan-

nels in vascular smooth muscle cells that, in turn, allow

calcium ions to enter the smooth muscle cell to induce

contraction. Myogenic autoregulation has been shown in

both retinal [68,103,158,163,174] and ONH circulation

[204,205] and in a variety of animal models.

Neurogenic or CNS factors are also thought to control

blood supply in certain ocular vascular beds [144] and in

response to light flicker simulation [167]. However, the

inner retina and the prelaminar portion of the ONH

lack an autonomic nerve supply and the resistance of

these vessels is altered primarily based on local metabolic

needs [28,82]. A vascular regulatory role for NO in the

human retina has been suggested, as basal retinal vessel

tone and flicker-induced dilation are inhibited by NO

synthase [7,15,38,72,74,112,143,183]. Earlier studies in pigs

[12,36,61] have shown that NO release is involved in regu-

lating the basal tone of retinal vessels; however, only hyper-

capnia and hypoxia failed to elicit NO-mediated dilation. It

is unknown whether other perturbations or local regulatory

responses in the retina are regulated via NO release in the

pig.

Hormonal factors also participate in the regulation of

blood flow by the signaling of smooth muscle cells, endo-

thelial cells, and also pericytes of a blood vessel [73,144].

In particular, the renin–angiotensin system activates AT-I

to form AT-II by the action of ACE [75,165]. AT-II infu-

sion has been shown to decrease ONH blood flow in cats

[189]. Inhibition of ACE improved retinal endothelial func-

tion in rats with oxygen-induced diabetic retinopathy [30]

and in healthy humans [145]. Epinephrine is produced by

the adrenal medulla and can produce tissue vasoconstric-

tion in the eye through adrenergic receptors [73,208].

However, the effect of epinephrine on retinal and ONH

circulation is not well understood. High levels of circulat-

ing epinephrine fail to produce greater changes in the reti-

nal vascular tone [101]. Similarly, the role of other

hormonal regulators such as vasopressin and natriuretic

peptides are not well established in the retina and ONH

[144].

In the eye, the retina and the ONH have been generally

shown to autoregulate up to an IOP of 45–50 mmHg in

healthy human subjects [150,169,173,185]. In addition,

Lovasik et al. [122] showed that choroidal blood vessels

also autoregulate during an OPP increase of 43% achieved

using isometric exercise. Several review papers have sug-

gested a disturbance of autoregulation in POAG

[25,41,45,46,48,65,66]. There is a lack of an adequate

evidence base, however, to prove an association between

direct evidence of altered autoregulation and of POAG.

REGULATION OF BLOOD FLOW INRESPONSE TO CHANGE IN PERFUSIONPRESSURE IN POAG

Altered autoregulation has been shown in NTG (previously

treated) and POAG in response to changes in perfusion

pressure (i.e., induced by exercise or changes in IOP)

[67,157]. A similar result was found in a study that mea-

sured change in choroidal pulsation and ONH blood flow

using the FPA and the laser Doppler flowmetry, respec-

tively, in response to a 20-mmHg increase in IOP in

patients with POAG [203]. A short-term increase in IOP

has been shown to cause a reduced regulatory change in

retinal arteriolar and venular diameter in POAG when

assessed using the RVA [136].

VASCULAR REACTIVITY RESPONSE TOINHALED GAS PROVOCATION INGLAUCOMA

Vascular dysregulation has been proposed as an important

factor contributing to GON, in addition to increased IOP

[45] [144]. The change in hemodynamic parameters in

response to provocation such as CO2, oxygen, cold stress,

or light flicker is termed vascular reactivity or metabolic

autoregulation. This functional assessment of the ocular

vasculature is thought, but not proven, to reflect vascular

regulation capacity. Relatively few studies have been under-

taken on the assessment of vascular reactivity in response

to provocation in patients with glaucoma. However, several

recent studies have provided some in-sight into the retinal

vascular response in glaucoma.

HYPERCAPNIA

Hypercapnia is the increase in the partial pressure of arte-

rial CO2 achieved by inspiring increased amounts of CO2.

In normal control subjects, breathing CO2 causes vasodila-

tion and thereby leads to an increase of inner retinal and

superficial ONH blood flow [26,37,117,175,197,198]. The

mechanism involved in the vasodilation response of blood

vessels to hypercapnia is controversial. Studies have shown

a positive role of NO in humans [181] and animal models

[180]. Conversely, an absence of the role of NO during

hypercapnia-induced vasodilation has been reported in ani-

mal models [36,61].

Hosking et al. [90] showed an increase in blood velocity

of the SPCA in response to hypercapnia measured using

CDI, although a similar response was not found in the OA.

Patients with (u)POAG have been shown to demonstrate a



normal increase in the blood velocity of the CRA to hyper-

capnia but a decrease in blood velocity in the OA [188].

Interestingly, others have found an exaggerated response to

hypercapnia in the CRA and SPCAs in NTG compared to

control subjects [85]; the authors explain that this might

be due to the reduced baseline blood velocity in the patient

group compared to controls. A recent study has shown a

decrease in the choroidal blood flow and an increase in

ONH blood flow measured using the laser Doppler flow-

meter in female patients with vasospastic symptoms, such

as cold hands and ⁄ or feet, in response to hypercapnia [69],

although there was no increase in ONH blood flow in con-

trol patients without vasospasm. The reason for these unex-

pected results is unclear. The authors speculate that there

might be either an increased response of the ONH to

hypercapnia in vasospasm or a lack of adequate autoregula-

tion causing an increase in blood flow due to the associated

change in blood pressure.

The majority of the hypercapnia studies have used a sim-

ple manual addition of CO2 rather than a re-breathing cir-

cuit. The use of a standardized provocation is essential to

minimize variability in the magnitude of vascular reactivity

and the re-breathing circuit helps to minimize this variabil-

ity [97]. Breathing CO2 results in an unpredictable increase

in ventilation and thereby an unpredictable increase in

PETO2 [166]. The use of normoxic ⁄ isoxic hypercapnia is

important in the assessment of retinal vascular reactivity in

order to avoid the confounding effects of varying O2, i.e.,

resulting in vasoconstriction. It has recently been shown

that the use of a nonrebreathing circuit and the addition of

CO2 to inspired air to induce hypercapnia results in an

increase in PETCO2 to target levels; however, the arterial

partial pressure of CO2 remains unchanged [97]. This

potential problem could be avoided by the use of a sequen-

tial gas breathing circuit and a newly developed gas flow

controller in our laboratory [97,199], which has allowed us

to produce a standardized normoxic hypercapnic stimulus

[199]. This standardized stimulus was then used for investi-

gating its effect on retinal arteriolar and ONH hemo-

dynamics in patients with (u)POAG, pPOAG, and controls.

The study showed that patients with (u)POAG and pPOAG

show a reduced magnitude of retinal vascular reactivity to

normoxic hypercapnia compared to the other groups

[200].

HYPEROXIA

Hyperoxia is the increase in the blood arterial partial pres-

sure of oxygen. The ocular vasculature responds to this

increase in oxygen level by vasoconstricting which results in

a decrease in blood flow in healthy humans [26,62,109,124].

The response to hyperoxia in glaucoma has not been widely

studied. This is likely due to the theory of a pre-existing

vasospasm in glaucoma and that breathing O2 would further

decrease the blood supply to an already compromised ONH.

Recently, retrobulbar velocities in patients with POAG have

been shown to remain unaltered in response to hyperoxia,

suggesting that the pre-existing vasospasm prevents further

decrease in blood velocity in this group [90]. There is also

evidence that glaucoma might be associated with reduced

blood velocity in cerebral vessels, in particular, the middle

cerebral artery and also a decrease in the magnitude of cere-

bral vascular reactivity to hyperoxia in POAG [86].

The increase in PETO2 during hyperoxia can generally

result in a concomitant change in PETCO2. Most previous

studies have used nonstandardized hyperoxic stimuli, includ-

ing the use of a nonrebreathing valve and the manual addi-

tion of small amounts of CO2. This resulted in a high

intrasubject variability. Gilmore et al. [63] used a sequential

re-breathing circuit and induced isocapnic hyperoxia to

assess retinal vascular reactivity. As a result, they demon-

strated a reduced variability of PETCO2 and this produced

less-variable vascular reactivity responses of the retinal vascu-

lature to hyperoxia. However, although now experimentally

feasible, the use of isocapnic hyperoxia has generally been

avoided in patients with glaucoma due to the risk of further

constriction of the vasculature of the retina and ONH.

FLICKER STIMULATION

The retinal and ONH blood vessels respond to flicker prov-

ocation with an increase in diameter and blood flow

[55,56,155,168]. A recent study has shown decreased vaso-

dilation in response to flicker in patients with type 2 diabe-

tes [5]. The mechanism of vasodilation response during

flicker is not well understood. In the cerebral vasculature,

however, it is believed that there is a tight neural coupling

between the local metabolic demand and blood flow [178].

In addition, there are various vasoactive factors identified

in the cerebral response to flicker stimulation, such as CO2,

potassium, adenosine, and NO, which have been suggested

to play a role in the vasodilatory response during neuro-

nal-driven activity in both the cerebral and retinal vessels

[33,38,93]. It is suggested that the increase in blood flow in

the ONH in response to flicker stimulation in healthy indi-

viduals might be an effect of increased retinal activity

[167,171]. However, the mediators responsible for the vaso-

dilation during this neural activity are still not clear,

although NO might play an important role [15].

Recently, the response of the retina and the ONH to

flicker stimulation has been widely studied in glaucoma.

Horn et al. [89] investigated temporal contrast sensitivity

in patients with glaucoma and normal controls and showed

a delayed recovery time after flicker stimulation in the

patient group compared to controls. Vascular reactivity of

the retinal and ONH blood vessels measured using laser



Doppler flowmetry in response to flicker stimulation was

reduced in patients with treated early glaucoma but did

not show any deterioration in patients with ocular hyper-

tension [172]. Similarly, another study showed reduced

magnitude of vasodilation in retinal veins in response to

flicker stimulation in patients with previously treated early

glaucoma [58].

A short-term increase in IOP in a group of normals does

not alter the dilation response to flicker stimulation [56].

This is in agreement to previous experiments in animal

models [15,170]. However, these findings cannot be directly

compared to patients with glaucoma because the long-term

effect of increased IOP has not been studied. Recently, an

abnormal autoregulatory response to flicker and pattern

stimulation has also been reported in early glaucoma [167].

COLD STRESS TEST

Cold provocation is a technique used to assess the function

of the ANS. Disturbance in the ANS might be present in

glaucoma, in particular in NTG [13,29,114]. Cold provoca-

tion generally produces vasoconstriction and a decrease in

peripheral blood flow.

Previous studies in patients with POAG showed no signif-

icant alteration in ocular blood flow assessed using SLDF

and trans-cranial Doppler in the peripapillary retina [140]

and in the OA [176]. Recently, patients with POAG have

been shown to exhibit a decrease in blood flow at the tem-

poral neuroretinal rim in response to cold provocation,

whereas no change was found in ocular blood flow in non-

glaucomatous subjects [60]. The mechanisms responsible for

the regulation of blood flow during cold provocation are not

well understood. However, Nicolela et al. [140] have shown

increased levels of plasma ET-1 in POAG after cold provoca-

tion. This increase in ET-1 may be responsible for the vaso-

constriction of peripheral blood flow in response to cold in

POAG. The use of IOP reducing treatment in patients with

POAG and vasospasm helped to improve ONH rim blood

flow compared to those without vasospasm [78].

A limiting factor in our interpretation of virtually all

vascular reactivity studies is a lack of understanding of the

impact of the provocation upon the cellular signalers that

control ocular vasoconstriction and vasodilation.

VASCULAR ENDOTHELIAL FACTORS INGLAUCOMA

The vascular endothelium lines the lumen of blood vessels

and, in terms of arterioles, is enveloped in the vascular

smooth muscle cells [28,73]. It regulates blood flow by pro-

ducing vasoactive substances such as EDCF and EDRF

(Figure 2). In healthy individuals, the endothelial factors

respond to various provocative stimuli to maintain local

blood flow, in the face of change in blood pressure by exer-

cise [39,95,121,122,156] or changes in IOP induced using a

suction cup [68,150,156,169], and also to maintain the sup-

ply of nutrients based on local metabolic demands

[82,112,130,144,154,158].

The EDCFs are derived from the cycloxygenase pathway

and can produce constriction by the release of contracting

factors such as PGH2 and thromboxane A2, as studied in

the cerebral vasculature [43,123,125]. In the ocular circula-

tion, prostanoids (end products of PGH2) have been shown

to be involved in the regulation of blood flow in newborn

piglets in response to increase in perfusion pressure [80].

In addition, AT-I after conversion into AT-II by ACE can

also result in vasoconstriction in the retinal circulation

[123]. The cycloxygenase pathway, however, also produces

prostacyclin by the activation of the enzyme phospholipase

A2 and results in vasodilation through an increase in cAMP

[144].

Among the various dilating and constricting factors,

there is some evidence that NO (EDRF) and ET-1 (EDCF)

represent major contributors responsible for the modula-

tion of blood flow in the eye. A constant balance between

these two opposing factors is critical for proper regulation

of the vascular system [21,128,147]. NO and ET-1 are

continually secreted by the endothelium. Up-regulation of

ET-1 is thought to result in vasoconstriction, as will down-

regulation of NO, and vice versa. A possible disturbance of

this balance between NO and ET-1 has been proposed in

glaucoma, in particular in POAG, and this disturbance has

been suggested to trigger a series of events that lead to

GON [24,47,66,69,157,164]. A recent study [92] showed

that baseline ET-1 levels were lower in patients with

(u)POAG compared to pPOAG and controls. This is the

Figure 2. Schematic representation of the vasoconstricting and

vasodilating factors released by the vascular endothelium in response to

local physiological provocations. AT, angiotensin; EDHF, endothelium

derived hyperpolarizing factor; ET, endothelin; NO, nitric oxide; PG,

prostaglandin.



first study to show an overall reduction in ET-1 level in

(u)POAG. Correlation analyses also demonstrated that

ET-1 and cGMP are involved in the regulation of blood

flow in POAG. Clearly, there is need for more research to

better understand the mechanisms involved in the regula-

tion of blood flow.

ENDOTHELIALDERIVED CONSTRICTINGFACTORS

The endothelial cells produce ET, a 21 amino acid peptide.

There are three isoforms of ET, namely, ET-1, ET-2, and

ET-3 [24,133,144]. ET-1 is the primary constricting factor

that has been widely studied and is thought to be produced

in large amounts in the ocular circulation. ET-1 mainly

causes vasoconstriction by the stimulation of the ET-A

receptor that is present in the vascular smooth muscle cells

and pericytes and is thought to increase intracellular cal-

cium [73,129,160]. At lower concentrations, ET-1 through

the stimulation of the ET-B receptors can result in vasodi-

latation via the prostacyclin pathways [129].

Recently, a link between increased IOP and factors that

might drive GON was investigated. The aqueous ET-1 con-

centration increased as a result of increase in IOP that pos-

sibly suggests the role of ET-1 in GON [159]. Also, higher

ET-B receptors immuno-reactivity was observed in patients

with glaucoma than controls. This also supports the exist-

ing theory of the potential involvement of ET-1 in the

pathogenesis of glaucoma. [202]. Hyperoxia results in vaso-

constriction of retinal blood vessels and this is primarily

mediated by ET-1 [32,193,211]. Intravitreal or intravenous

injection of ET has been shown to decrease retinal blood

flow in animals [16,64] and in humans [182]. ET can also

reduce the bio-availability of NO, thereby leading to exag-

gerated vasoconstriction [128]. ET-1 has been suggested to

be present in higher amounts in the plasma and ⁄ or aque-

ous of patients with glaucoma, in particular NTG [22,192]

and in POAG with visual field progression [40]. However,

no difference was found in ET-1 reported in POAG by

another study [115] and in NTG [104]. An increased aque-

ous level of ET-1 was also reported in hypertensive dogs

[106]. Similarly, Tezel et al. [194] showed higher levels of

aqueous ET-1 in humans with POAG. However, few other

studies have failed to show higher levels of plasma ET-1 in

NTG or POAG [88,115,140,194] (Table 1). In addition,

Nicolela et al. [140] were the first to investigate plasma

ET-1 concentration following cold provocation and showed

higher ET-1 levels in patients with glaucoma. The discrep-

ancy in the results of these studies might be due to the dif-

ference in the characteristics of the sample studied and also

differences in the procedures of the assay (i.e., radioimmu-

noassay and enzyme immunoassay) used and also individ-

ual variations in the cross-reactivities of the immunoassays.

The findings of Kunimatsu et al. [115] might differ from

other studies in the respect that ET-1 levels were assessed

in a Japanese population and also in patients of age

<60 years. It is thought that ET-1 levels might increase

with age; however, this needs to be confirmed [194].

Most of these studies have included patients receiving

ocular hypotensive treatment prior to ET-1 assessment.

The influence of IOP lowering medications on endothelial

vasoactive factors is not known; however, we cannot rule

out the possible effect of treatment on these findings.

A recent study has shown a reduced magnitude of vascular

reactivity in response to normoxic hypercapnia in

(u)POAG and also in pPOAG compared to age-matched

control. However, topical treatment with 2% Dorzolamide

only for two weeks in the (u)POAG group improved reti-

nal vascular reactivity to a similar extent as the control

group. There was no significant change in the OPP between

pre- and post-treatment with 2% Dorzolamide, suggesting

that the improvement of vascular reactivity in POAG fol-

lowing Dorzolamide treatment was due to a direct pharma-

cological effect of the drug on the retinal vasculature [200].

Dorzolamide inhibits the action of carbonic anhydrase in

the nonpigmented epithelium of the ciliary body, the

enzyme that is mainly responsible for creating the trans-

membrane ionic gradient that in turn generates the secre-

tion of aqueous humor. In addition, to the IOP lowering

effect of dorzolamide, this drug has been suggested to

increase the homeostatic ocular blood flow as a result of

reduced external tissue pressure, although a direct effect of

dorzolamide on the retinal vessels cannot be excluded as

inhibition of carbonic anhydrase may result in an increase

of intra-cellular CO2 and subsequent vasodilation and ⁄ or

an improved vascular reactivity response [148,190]. Other

vasoconstricting factors are present in the cerebral circulation

Table 1. Summary of findings from various studies that

investigated plasma ET-1 levels (a) in NTG compared with controls

and ⁄ or high-tension glaucoma*, and (b) in POAG compared to

controls and ⁄ or capsular glaucoma�

Author [ref.] Findings

(a)

Kunimatsu et al. [115] No difference in ET-1 levels

Cellini et al. [22] Higher ET-1 levels

Kaiser et al. [104] No difference in ET-1 levels*

Sugiyama et al. [192] Higher ET-1 levels

(b)

Kunimatsu et al. [115] No difference in ET-1 levels

Emre et al. [40] Patients with progressive visual

fields had higher ET-1 levels

Nicolela et al. [140] No difference in ET-1 levels

Hollo et al. [88] No difference in ET-1 levels�Tezel et al. [194] No difference in ET-1 levels



such as PGs, superoxide anions, and thromboxane A2 [196];

however, there is little evidence of the involvement of these

factors in the regulation of the ocular circulation.

ENDOTHELIALDERIVED RELAXINGFACTORS

The vascular endothelium produces NO, a potent vasodila-

tor, under basal conditions and also in response to provo-

cation [38,73,74,102,147]. NO is formed from l-arginine by

the enzyme NOS [17,96]. There are three types of NOS:

namely, eNOS, iNOS, and nNOS. eNOS is the most widely

available form in the vascular endothelium and is responsi-

ble for the regulation of blood flow [138,153]. The release

of NO during provocation results in the increased produc-

tion of cGMP leading to a decrease in calcium, thereby

causing vasodilatation [53,76,77].

Previous research has already shown the effect of NO on

the regulation of choroidal blood flow [34,183]. It is well

established in the cerebral circulation that NO contributes

to hypercapnia-induced vasodilatation [137,146,181,201].

However, a few recent studies do not support the above

results [84,177]. Furthermore, the effect of NO on the ocu-

lar circulation has not been as extensively studied. NOS

inhibition did not significantly decrease the hypercapnia-

induced retinal vasodilatation in humans [181], whereas a

positive role of NO during hypercapnic vasodilation was

reported in cats [180]. Recently, it was reported that NO

plays a role in the recovery (i.e., postvasoconstriction) of

retinal arterioles after hyperoxia [98].

NO has a very short half-life and direct measurement is

challenging. As a result, previous studies have investigated

the presence of cGMP or levels of nitrites and nitrates in

the aqueous and plasma as a surrogate to ascertain the level

of NO expression but the results are generally inconclusive.

There is some evidence for decreased levels of NO in the

plasma ⁄ aqueous of POAG [35,53,111,142]. However, other

researchers have reported no difference in the plasma levels

of NO [106,113]. Studies using other types of glaucoma,

such as juvenile and neovascular glaucoma, showed that

NO levels in the aqueous were higher in NVG, whereas they

were lower in juvenile glaucoma [23]. Similarly, Tsai et al.

showed increased levels of nitrites in the aqueous of patients

with NVG [212] (Table 2). NVG, a secondary glaucoma, is

generally associated with other systemic conditions, in par-

ticular diabetes [118]. It is known that the ocular blood ves-

sels are in a dilated state due to the hypoxic environment in

NVG [110] and that is the possible reason for the increase

in NO or its surrogate marker levels in NVG.

There is evidence of an imbalance of NO or its surrogate

markers in glaucoma compared to healthy controls. The

measurement of indirect markers to represent NO has

some disadvantages as it is hard to eliminate the influence

of diet rich in nitrates that will artificially elevate nitrites,

nitrates, and cGMP levels in the plasma. Previous reports

lack details about any diet restrictions imposed in study

patients other than the study by Galassi et al. [53] and

Hudson et al. (2008) [92]. It is yet to be confirmed

whether the levels of nitrates, nitrites, or cGMP reflect NO

expression.

CONCLUSIONS

There is evidence that vascular dysregulation is an impor-

tant factor in the pathogenesis of glaucoma in particular

POAG including NTG. The alteration of ET-1 and NO lev-

els in both the plasma and aqueous humor of patients with

POAG and NTG also supports this hypothesis; however,

the results from many of these studies are contradictory.

Most previous work has investigated homeostatic hemody-

namic parameters in POAG and other types of glaucoma

rather than the measurement of the hemodynamic response

to a provocation. The measurement of baseline blood flow

provides little, if any, information about the vascular regu-

lation characteristics of retinal and ONH blood vessels in

response to changes in local metabolic demands. In the

future, there is a need to focus on the comprehensive

assessment of ocular hemodynamic parameters in response

to various standardized provocations, in order to better

understand the pathophysiology of GON. In addition, the

involvement of various EDCF and EDRF that are thought

to regulate retinal and ONH blood flow needs further

Table 2. Summary of findings from various studies that

investigated (a) aqueous NO levels (indirect markers of NO such as

cGMP, nitrates, and nitrites) in POAG compared to controls and ⁄ or

patients with angle closure glaucoma*; and (b) plasma NO levels

(indirect markers of NO such as cGMP and nitrites) in POAG, NTG�,

and NVG� compared to controls and ⁄ or patients with chronic angle

closure glaucoma§

Author [ref.] Findings

(a)

Kallberg et al. [106] Increased levels of nitrites in

dog models

Galassi et al. [53] Decreased levels of cGMP

Kosior-Jarecka et al. [111] Decreased levels of nitrites*

Doganay et al. [35] Decreased levels of nitrites

Kotikoski et al. [113] Trend to increase in nitrite and

cGMP levels

Tsai et al. 2002 Increase in NO levels*

(b)

Galassi et al. [53] Decrease in cGMP levels

O’Brien et al. [142]� Decreased concentration of cGMP

Kotikoski et al. [113] Increase in cGMP levels

Tsai et al. 2002� Increase in NO levels§



investigation. A standardized assay procedure that quanti-

fies the levels of endothelial biomarkers is required for

direct comparison of results between studies. The possible

association of the plasma ⁄ aqueous levels of the endothelial

constricting and relaxing factors to functional vascular

reactivity also remains to be established in patients with

glaucoma (Table 3). Recent and future developments in the

methods to assess retinal hemodynamics and in inspired

gas provocation techniques will provide an opportunity to

establish the vascular regulation response of the retinal vas-

culature and thereby correlate changes in the magnitude of

endothelial constricting and relaxing factors to the magni-

tude of vascular reactivity.

ACKNOWLEDGMENTS

This work was funded by the Canadian Institutes of Health

Research (Operating Grant to JGF and CH), Glaucoma

Research Society of Canada (to CH, JGF, and STV), and

American Optometric Foundation, William C. Ezell fellow-

ship (to STV). CH is a patent holder of the automated gas

flow controller instrument and shareholders in Thornhill

Scientific Inc.

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Vascular Reactivity of Optic Nerve Head and Retinal Blood Vessels in Glaucoma - A Review

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