Autoregulation refers to the ability of the cardiovascular system to modify vascular resistance in order to allow a constant blood supply to be maintained despite variations in perfusion pressure 151. It operates to ensure tissues and organs receive an adequate blood supply despite variations in hemodynamic conditions and has been demonstrated in both the retinal 86, 152 and ONH circulation 94 as well as, to a lesser extent, in the choroidal circulation 81.
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The most common method of evaluating autoregulatory function is through assessing the response of the ocular and systemic vasculature to provocation. This provocation can take the form of posture changes, artificial lowering of IOP, cold provocation, hand grip testing, flicker light stimulation or induced hypoxia and hypercapnia. Such provocations put the vascular system under stress and should evoke an
autoregulatory response which allows maintenance of normal ocular perfusion, a failure to observe this autoregulatory response is indicative of disturbed
autoregulation.
Although the exact mechanisms underlying autoregulation are still unclear, metabolic, myogenic, neurogenic and humoral factors are all known to trigger autoregulatory responses in the ocular circulation, as are endothelial derived vasoactive agents 151,
153, as summarised in figure 1.7.These autoregulatory triggers and their responses
are outlined in the following sections
Figure 1.7: Summary of the factors which trigger autoregulation of blood flow in the ocular circulation Myogenic factors Circulating hormones Autonomic nerves Endothelial agents Metabolic factors Endothelium Vascular smooth muscle
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1.4.3.1 Metabolic autoregulation
Metabolic autoregulation refers to the regulation of blood flow in accordance with tissue metabolite concentration. A tight coupling mechanism is thought to exist between tissue metabolism and ocular perfusion 151, with alterations in the local concentrations of metabolites including oxygen (O2) and carbon dioxide (CO2) 154, 155,
potassium (K+), hydrogen (H+) 156 and adenosine 157 having been shown to influence ocular vascular tone.
Partial oxygen pressure (pO2) has been identified as one of the main driving forces of
metabolic autoregulation 158, 159. Under conditions of systemic hyperoxia and hypoxia autoregulatory mechanisms act to maintain retinal and ONH O2 at constant levels.
Hyperoxic conditions trigger retinal arteriolar vasoconstrictions, reducing retinal blood flow and pO2154, 160 and hypoxic conditions trigger retinal arteriolar vasodilations,
increasing retinal blood flow 161 and allowing normalisation of pO2. The hemodynamic
response of the retinal vasculature to hyperoxia is thought to be mediated by
endothelin 162, whereas the hypoxia-induced vasodilation of the retinal vasculature is thought to involve endothelial derived prostaglandins and/or adenosine 163-166. The choroidal vasculature, in comparison, has been demonstrated to show little or no alterations in response to changes in blood oxygenation 167, 168.
Under conditions of hypercapnia, in which the partial pressure of CO2 (pCO2) is
increased, metabolic autoregulatory mechanisms have been demonstrated to function in the retinal, ONH and choroidal circulation bringing about a vasodilatory response of the vasculature which results in an increase in blood flow and pO2167, 169, 170. The exact mechanism behind hypercapnia induced vasodilation is still the subject
of debate, however it is thought that interactions between nitric oxide (NO) and endothelial derived prostaglandins play an important role 171.
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1.4.3.2 Myogenic autoregulation
Myogenic autoregulation refers to the regulation of blood flow in response to
alterations in systemic BP and allows a constant blood flow to be maintained despite variations in BP 151. The myogenic response was first described by Bayliss in 1902 and is characterised by a decrease in vessel diameter following an increase in transmural pressure 172. Its primary function in the body is to maintain the Starling equilibrium for capillary fluid exchange; however it is unclear whether this is also its primary function in the eye 173. Myogenic autoregulation is on the whole considered to be mechanically independent of the endothelium and intrinsic to the vascular smooth muscle cells (vSMCs), whereby stretching of the vessel wall is thought to lead to depolarisation of the vSMC membrane and vascular constriction 174. In the cerebral and renal circulation however myogenic induced vasoconstriction has also been suggested to be at least partly mediated by endothelial factors 175. Whilst myogenic regulation has been demonstrated in the ONH and retina 176 it is unclear whether myogenic mechanisms are also involved in the regulation of choroidal blood flow 173.
1.4.3.3 Neurogenic control
The eye has a rich autonomic innervation however this only extends to the uvea, PCAs and the extraocular portion of the CRA 177-179 and does not include the retina and prelaminar portion of the ONH 179, 180. Neuronal regulatory mechanisms are therefore suggested to play a key a role in the regulation of choroidal blood flow but have little effect on retinal or ONH blood flow 181, 182, despite alpha and beta-
adrenergic receptors having been identified in the retinal vessels 183, 184.
Sympathetic stimulation of the choroid, via sympathetic nerves originating from the superior cervical ganglion, triggers constriction of the choroidal blood vessels and increases choroidal vascular resistance, reducing blood flow 80, 182. It has been suggested that this vasoconstriction response of the uveal vasculature may function to protect the eye against overperfusion during periods of increased HR or BP 185 and
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indeed there is evidence demonstrating that under conditions of exercise, where sympathetic activity is increased, a regulatory vasoconstriction response of the choroidal vasculature allows maintenance of a constant blood flow in the face of an increase in OPP 81, 186. Numerous agents have been implicated as mediators of this neuronal regulation including acetylcholine 187, noradrenaline 187, vasoactive intestinal polypeptide 188, substance P 189 and NO 190, however the exact role played by each of these agents in ocular circulation physiology is still unclear.
Parasympathetic nerves reach the eye through the oculomotor nerve, facial nerve and through the ophthalmic and maxillary divisions of the trigeminal nerve 78, 178 and there is evidence to suggest that parasympathetic innervation can stimulate a vasodilation response in the choroidal vasculature and increase blood flow. This evidence is variable however, as whilst intracranial stimulation of the facial nerve has been demonstrated to cause significant vasodilation in the choroid 80, 191, electrical stimulations of parasympathetic nerve fibres of the ciliary ganglion, although inducing intense miosis, have not been found to notably change the uveal vascular resistance
182. The role of parasympathetic innervation in ocular neurogenic regulation is
therefore uncertain.
1.4.3.4 Humoral Control
Humural control refers to the potential regulatory influence of numerous vasoactive agents present in the circulating blood which, through either direct interaction with the vascular smooth muscle cells (vSMCs) and pericytes or through mediation of
endothelial cells 192, could influence OBF. Angiotensin and catecholamines for example, which are both circulating hormones, have been suggested to influence retinal and choroidal circulation, however the evidence is variable. Indeed whilst angiotensin-II receptor binding sites have been identified in ocular tissue 193,
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of data seems to suggest that in human healthy subjects this system does not play a major regulatory role 173, 195. Furthermore a similar uncertainty surrounds the role of catecholamines in OBF regulation after both a decrease 196 and an increase 197 in retinal perfusion following administration of adrenergic drugs has been demonstrated. Therefore whilst the potential influence of circulating and local hormones should not be discarded the evidence suggests that they are unlikely to have a major impact on the regulation of the choroidal and retinal blood flow. Furthermore the presence of the BBB prevents direct contact between the circulating blood and the retinal and ONH vSMCs indicating that the role of circulating hormones in the regulation of ONH blood flow in particular may be even less; however some diffusion of molecules from the choroidal vasculature may occur in the prelaminar region of the ONH due to the structural differences in this region (see section 1.2.3.3).
1.4.3.5 Endothelial dependent regulation of vascular tone
The vascular endothelium is an important mediator of vascular tone, releasing vasoactive agents both under basal conditions and in response to various chemical and mechanical stimuli. These vasoactive agents are commonly referred to as endothelial derived constricting factors (EDCF) and endothelial derived relaxing factors (EDRF) and they play an important role in the regulation of OBF 156. The endothelium and its regulatory roles are discussed in more detail in the following section.