 reduced ocular perfusion pressure is a risk factor for the prevalence , incidence and progression of glaucoma .  the death of retinal ganglion cells appears to involve primary and secondary insults . 
glaucoma is a family of multifactorial optical neuropathies characterized by loss of retinal ganglion cells ( rgcs ) leading to typical optic nerve head ( onh ) damage and distinctive visual field defects .
although the pathogenesis of the disease is unknown , it is well established that the main risk factor for glaucoma is elevated intraocular pressure ( iop ) .
reducing iop is effective in slowing down the progression of the disease but some patients still progress despite adequately controlled iop .
several studies implicated vascular risk factors in the pathogenesis of glaucoma , blood pressure ( bp ) and ocular perfusion pressure ( opp ) being the most studied .
this vascular hypothesis is based on the premise that abnormal perfusion and the subsequent ischemia of the onh play a major role in the glaucomatous damage .
as such the opp can be estimated as the difference between the arterial pressure and iop .
some studies indicate that systemic hypertension is a risk factor for glaucoma [ 13 ] .
on the other hand some studies indicate that low systemic bp is a risk factor for development and progression of glaucoma .
a direct and clear relationship between bp level and glaucomatous damage has , however , not been established .
the good irrigation of the ocular tissues is ensured by an adequate opp depending on a complex regulation process that balances bp and the iop . as such dealing with the concept of opp and bp at the same time
large epidemiological studies have shown that low opp is a risk factor for the prevalence , incidence and progression of glaucoma . in the barbados eye study  
subjects with the lowest 20% of diastolic perfusion pressure were 3.3 times more likely to develop glaucoma . in the proyecto ver study   it was established that patients with a diastolic perfusion pressure as low as 45  mmhg had a three times greater risk of developing glaucoma compared to those with a diastolic perfusion pressure of 65  mmhg .
this is in keeping with data from the egna  neumarkt study   showing that the prevalence of the disease in patients with diastolic perfusion pressure less than 50  mmhg increases 4.5 fold compared to patients with diastolic perfusion pressure of 65  mmhg .
data on glaucoma progression are available from the early manifest glaucoma trial ( emgt ) .
low systolic perfusion pressure was a predictor of progression with an almost 50% higher risk .
more in depth reviews on the data linking opp to glaucoma prevalence , incidence and progression have been provided .
this review , however , will formulate some hypotheses as to why opp is a risk factor .
vascular factors have been identified in many chronic neurodegenerative disorders including alzheimer 's disease and amyotrophic lateral sclerosis . in glaucoma
the hypothesis of a vascular involvement in the disease process has been formulated a long time ago .
the evidence that low opp is a risk factor for the disease has further supported this concept .
indeed it assumes that mean arterial pressure ( map ) as measured at the brachial artery is a good measure of map at the level of the ophthalmic artery .
in addition , there is evidence that the difference between venous pressure and iop is increased in patients with glaucoma .
this is related to the phenomenon of spontaneous venous pulsations in the central retinal vein , which appear to be a risk factor for glaucoma .
as such it is likely that the relationship between true opp and glaucomatous damage is much stronger than indicated above . whilst it is well - established
that reduced opp ( as currently estimated ) is a risk factor for glaucoma there is considerable controversy as to why this is the case . in the following
we present a theory describing pathways that may depend on opp and contribute to glaucomatous damage .
as indicated in figure 1 we assume that loss of rgcs is the consequence of primary and secondary insults as suggested previously .
the site of primary insult to rgc axons in glaucoma is most likely within the onh , more specifically at the lamina cribrosa .
increased iop may be responsible for this loss of rgc axons modulated by the biomechanical properties of the ocular tissues   and the level of cerebrospinal fluid pressure ( csf ) [ 1820 ] .
as such , low csf pressure may be one of the factors by which opp modulates the risk of glaucoma because changes in either of them lead to a change in the trans - lamina cribrosa pressure gradient .
another factor in the primary glaucomatous insult that may be enhanced by low opp is onh ischemia associated with reduced flow of nutrients to the rgc axons .
some investigators assume that this ischemia at the onh is primary and at least in some cases associated with systemic disease .
another possibility is that iop - related strain within the peri - papillary sclera affects perfusion through the scleral branches of the short posterior ciliary arteries .
the vasculature of the onh is complex and the post - laminar regions of the onh are supplied by branches of the posterior ciliary arteries . owing to its deep anatomical location little is known about blood flow ( bf ) and its regulation in this part of the onh .
most quantitative data about onh bf regulation stem from the anterior onh regions that are supplied by the central retinal artery .
once a primary insult has occurred at the level of the onh rgcs appear to function at reduced energy levels with affected mitochondria .
this is supported by numerous experimental data   including electrophysiological studies in the primate revealing that affected rgcs retain some of their functionality . as such neuroprotective strategies
indeed targeting mitochondria may offer a wide range of strategies for rgc survival including the dynamic processes of mitochondrial fission and fusion , the electron transport chain components , ion channels and defense strategies against oxidative stress .
oxidative stress associated with extensive production of reactive oxygen species ( ros ) such as free radicals , hydrogen peroxide , or singlet oxygen is another factor that may be enhanced by ischemia associated with low opp .
free radicals are molecules containing unpaired electrons in their outer orbits . singlet oxygen and hydrogen peroxide
oxidative stress occurs when the balance between production of ros and endogenous antioxidative defense systems is disturbed either owing to increased ros activity or owing to reduced antioxidative capacity .
strategies may be wide and include inhibition of ros formation , administration and/or supplementation with antioxidants or with agents that increase the reducing power necessary for ros detoxification or stimulation of gene expression for increasing mitochondrial antioxidant defenses .
another pathway in which reduced opp may contribute is related to secondary insults associated with abnormal autoregulation or a breakdown in neurovascular coupling . here
it is assumed that rgcs that function at low energy states are susceptible to periods of ischemia or reduced nutritional support .
such periods can happen if opp falls below the lower autoregulatory limit or if the functional hyperemic reaction to visual stimulation is dysfunctional in patients with glaucoma .
autoregulation is the ability of a vascular bed to maintain its bf despite changes in perfusion pressure .
we have recently provided an in - depth review on the relation between opp and ocular bf   and as such only some of the aspects that are relevant for the present topic will be covered .
nowadays there is evidence that retinal , onh and choroidal bf show some regulatory capacity in response to changes in opp .
traditionally it is assumed that at the lower limit of autoregulation vessels are fully dilated .
this is , however , not the case because the hyperemic vasodilator response to flicker stimulation is fully preserved even below the lower limit of autoregulation
. the mechanisms of autoregulation are complex and not fully understood . in the retina and the onh
it appears that autoregulation is strongly dependent on myogenic and metabolic mechanisms . in the choroid the rich parasympathetic ,
sympathetic and sensory innervation as well as intrinsic choroidal neurons plays a key role in bf regulation in face of changes in opp . in glaucoma
this includes experiments in which iop was modified and studies in which the response to posture changes was assessed .
evidence for altered autoregulatory capacity in glaucoma also arises from group correlations between ocular bf and opp [ 3032 ] .
the reason for abnormal autoregulation in glaucoma patients is not fully understood ( figure 2 ) . obviously reduced opp as well as increased opp variability may lead to a fall of bf when the lower limit of autoregulation is reached .
increased variability of opp and nocturnal bp dipping have indeed been identified as risk factors for glaucoma .
evidence has accumulated that , at least in the choroid , bf regulates better when map is modified than when iop is modulated .
this means that at the same level of opp bf may also depend on the absolute value of map and iop .
the authors have developed a rabbit model in which map can be modulated by placing an occluder around the thoracic vena cava .
this allows for measurement of choroidal bf while opp is modified although iop is held constant .
interestingly bf regulated better when iop was kept constant at levels of 5  mmhg than at levels of 25  mmhg . in recent years we have performed several studies indicating that this is also the case in humans . as such any reduction in iop is associated with an improvement in bf regulation .
alterations in autoregulation in glaucoma may also arise from a phenomenon called primary vascular dysregulation .
this term was introduced by flammer describing otherwise healthy subjects that show abnormal regulation in response to temperature changes and mechanical or emotional stress .
the basis for this dysregulation is not clear , but may be related to vascular endothelial dysfunction .
in addition , both endothelin and nitric oxide ( no ) are key regulators of onh and choroidal bf at baseline and during isometric exercise . in the onh
this may be related to loss of autoregulation in glaucoma , because astrocytes are considered to play a key role in tissue remodeling of the onh .
it is , however , unclear how early this activation of astrocytes occurs although there is evidence that release of substances such as glutamate and tumor necrosis factor  from astrocytes is involved in rgc death . in the onh astrocytes
are involved in autoregulation during an increase in iop , because the gliotoxic agent l-2-aminoadipic acid modifies the bf response during the decrease in opp .
in the brain and the retina bf increases when neurons get active , a response called functional hyperemia . this phenomenon called neurovascular coupling has attracted much interest because an abnormal bf response to neuronal stimulation causes cell death caused by inadequate nutrient supply .
our understanding of the mechanisms that underlie neurovascular coupling has increased significantly in the recent years .
briefly , synaptically released glutamate activates n - methyl - d - aspartate receptors and metabotropic glutamate receptors in neurons and astrocytes , respectively .
this leads to an increase in intracellular ca activating arachidonic acid pathways associated with the synthesis of vasodilators such as prostaglandins and epoxyeicosatrienoic acids and vasoconstrictors such as 20-hydroxy - eicosatetraenoic acid .
in addition no synthesized from no synthase-1 in neurons may play a role in the vasodilator response . indeed , no synthase inhibition blunts the retinal hyperemic response to flicker stimulation in humans .
generally it is , however , believed that no has a modulatory rather than a mediating role in the human retinal neurovascular coupling , because the activity of the enzymes in the arachidonic acid pathways depend on the level of no .
as such the hyperemic response may also depend on endothelial no related to flow - mediated mechanisms . in glaucoma
the response of retinal and onh bf to flicker stimulation is reduced [ 5153 ] .
primary vascular dysregulation appears to be associated with abnormal retinal neurovascular coupling , because vasospastic subjects show a reduced response to flicker stimulation . in keeping with this idea endothelial dysfunction
the level of iop , however , does not appear to be directly related to the reduced hyperemic response , because short - term elevation does not influence flicker - induced vasodilatation .
activated astrocytes in glaucoma are also potential sources of impaired vasodilator response to flicker stimulation , although this hypothesis remains unproven . independently of the mechanisms contributing to reduced flicker responses in glaucoma
it may well be that abnormal neurovascular coupling plays a role in the secondary insults to rgcs as shown in figure 1 .
one of the reasons why our understanding of the relation between opp and glaucoma is still limited lies in the difficulties to measure retinal and onh bf [ 5558 ] .
doppler optical coherence tomography may become a technique capable of measuring bf in a valid and reproducible way [ 5961,62 ] .
this improvement in technology is associated with the hope of gaining more insight into ocular bf regulation .
it is pharmacologically difficult to increase opp . on the other hand one needs to be careful not to induce systemic hypertension with such approaches .
an exception may be reducing anti - hypertensive treatment in patients with systemic hypertension in order to prevent very low opps .
when neuroprotective strategies are implemented it appears that it is not enough to focus on the pathways that are involved in programmed cell death of rgcs ( figure 4 ) .
most probably neurovascular as well as neuroinflammatory pathways ( not described in this review ) need to be targeted as well . generally the pathways leading to primary and secondary insults in glaucoma need to be better described to target the neurovascular component in glaucoma .
papers of particular interest , published within the period of review , have been highlighted as: of special interest of outstanding interest  of special interest  of outstanding interest
 graphical abstracthighlights reduced ocular perfusion pressure is a risk factor for the prevalence , incidence and progression of glaucoma . 
  the death of retinal ganglion cells appears to involve primary and secondary insults .  
 reduced opp may enhance both primary and secondary insults . 
  abnormal autoregulation and neurovascular coupling may lead to ganglion cell death . 
Graphical abstract
Highlights
Introduction
Why is low OPP a risk factor for glaucoma?
Autoregulation
Neurovascular coupling
Conclusions and future directions
References and recommended reading