Atherosclerosis is a chronic, progressive vascular disease that may reduce the autoregulatory capacity of the optic disc.22 The occurrence of atherothrombosis in this disease may lead to impediment of BF. In a study performed on monkeys, Faraci et al.23 found that atherosclerosis increases the response of vascular endothelial cells for the activation of leukocytes and platelets. Extracellular transduction signaling provoking abnormalities in endothelial cell function appears to be the triggering mechanism for thrombus formation.24 Moreover, altered serotonin released by endothelial cells seems to play an active role in the impediment of BF. Hayreh et al.22 demonstrated in their study on atherosclerotic monkeys that the presence of serotonin during atherothrombotic pathogenesis induced vasospasm of the central retinal artery and posterior ciliary artery, consequently impairing BF. However, a cause-effect relationship between atherosclerosis and POAG has not been proven. In fact, the prospective, population-based Rotterdam Eye Study found atherosclerosis not to be a significant risk factor for POAG.25

Nevertheless, as a systemic process, atherosclerosis has recognized association with vascular conditions that have a possible correlation with POAG. For example, atherosclerosis is the most common pathologic process affecting the carotid system that leads to cerebrovascular accidents.26 It also shows a trend of high prevalence among patients with aortic valve stenosis that have experienced episodes of myocardial infarction.27 Both of these conditions have been demonstrated to have a relatively strong association with POAG.20,28,29

In brief, atherosclerosis appears to have some influence on OBF. It also appears to play a role in autoregulatory dysfunction of vascular conditions that have potential association with POAG. However, further investigation is necessary to comprehend how endothelial pathophysiology in atherosclerosis relates to ocular autoregulatory dysfunction in POAG.

Vasospasm is a reversible, exaggerated constriction or closure of blood vessels that leads to excessive reduction in BF.30,31 This excessive vasoconstriction usually results in insufficient oxygen supply to the surrounding tissue.31 Many vasospastic episodes arise secondary to underlying diseases such as prinzmetal's angina and multiple sclerosis.32 However, a primary vasospastic syndrome has also been identified in patients having such a predisposition when exposed to cold stimuli and emotional stress.33 These patients often suffer episodes of ocular vasopasm as well as other systemic vasospasmic manifestations such as cold extremities, migraine and low BP.33–35 Ocular vasospastic episodes have been related to glaucoma.33,34 Disturbances in BF to the ONH seem to occur in some glaucoma patients as a results of episodic local vasospasms.36 Moreover, systemic vasospasmic manifestations have been associated to glaucomatous deterioration.37–40 Nicolela et al.37 concluded in their study that glaucoma patients with evidence of vasospasmic effects in their extremities were more likely to show visual field deterioration after cooling stimulus than glaucoma patients without acral vasospasm. Hence, suggesting that vasospastic responses may be involved in glaucomatous progression.

Vasospasm of the brain vessels is linked to the pathogenesis of migraine.38 Migraine, a condition more commonly encountered in females, has a well documented association with glaucoma progression.39,40 In their respective studies, McKendrick et al. and the Collaborative Normal-Tension Glaucoma Study Treatment Group found that migraine is an independent risk factor for the progression of glaucomatous visual field loss.39,41 Furthermore, Drance et al.42 concluded from their visual field data collection analysis of 160 patients with normal tension glaucoma (NTG) that the occurrence of migraine in conjunction with NTG was more common in women. However, the study also concluded that gender and presence of migraine contribute separately to the risk of progression of visual field loss.42 Low BP has also been associated with vasospasm and considered a risk factor in glaucoma.33,35 However, low systemic pressure related to glaucoma may or may not be secondary to vasospasm. Pache et al.43 concluded in their study that vasospasm and low BP may be separate risk factors for glaucomatous damage. Nonetheless, it is a general agreement that non-physiologic nocturnal systemic pressure dipping causing marked circadian fluctuations in ocular PP is linked to vasospasm and glaucoma progression.44–46

This evidence suggests that vasospasm may represent a particular way by which glaucomatous damage can occur. Seemingly, an environment of dysregulated blood flow may result from these episodes, thus putting the ONH at a greater risk of ischemic damage.34 Furthermore, vasospasm may play a more significant role in POAG ONH damage than atherosclerosis. Atherosclerotic patients tend to overcome with more proficient autoregulation function the challenges of ocular perfusion.18 OBF fluctuates more dramatically in vasospastic patients due their susceptible hyper-responsiveness to cold stimuli and emotional stress, which may as well lead to reperfusion damage to the ONH.18,33,47

Endothelial vascular dysfunction is also implicated in the autoregulatory pathophysiology associated to POAG.47 Endothelial biochemical alterations initiated by oxidative stress are known to alter the vascular tone and destabilize vascular regulation function.48 Nitric oxide (NO) and endothelin-1 (ET-1) are the endothelial vasoactive mediators that sustain the physiological balance between vasodilator and vasoconstrictor pathways, respectively.49,50 NO is made available via endothelial cell synthesis and endothelin-B receptor (ETB) stimulation.12 ETB receptors activity is triggered through interaction with ET-1 that is synthesized and released by endothelial cells. ET-1 interacts primarily with endothelin-A receptor to mediate physiological vasoconstriction. A decrease in the biosynthesis and/or bioavailability of NO and an excess of ET-1 causes altered vasoreactivity (increased vasoconstriction), which leads to an imbalance in basal vascular tone.47,51

A number of vascular diseases that potentially contribute to the development and progression of POAG are associated with endothelium-dependent altered vasoreactivity.12 Dyslipidemia for example, has been associated with inhibition of endothelial NO signaling in many organs including the eye. Kawakami et al.52 demonstrated in a study performed in mice that apolipoprotein CIII in hyperlipidemia impairs insulin uptake by endothelial cells, necessary for the production of NO. A similar study demonstrated that mice lacking nitric oxide synthase (NOS), the enzyme present in endothelial cells that mediates the conversion of the amino acid L-argenine to NO, had hyperlipidemia.53 Likewise, faulty ET-1 activity provoking pathological vasoconstriction has been identified in conditions such as hypertension and diabetes.54,55

A series of studies have investigated the role of endothelial mediators in POAG. It has been demonstrated that intravenous administration of ET-1 reduces significantly retinal blood flow.56 From their study based on IOP increments in living isolated rat retinas, Rigosi et al.57 suggest that prolonged or recurrent IOP elevation may induce ET-1-mediated retinal capillary dysregulation contributing to neuronal damage overtime.

In a study evaluating glaucomatous field progression in 31 patients with POAG, specific radioimmunoessay revealed that 16 of these patients had increased ET-1 plasma levels.58 Another study observing the effect of dual endothelin receptor blockage on OBF reveals that oral administration of bosetan, a dual endothelin receptor antagonist, increases ocular blood flow in patients with POAG.59

Polak et al.60 demonstrated in their study on NOS inhibition of the ocular vasculature that patients with POAG yielded significantly less percent reduction of blood flow to the ONH than healthy controls. Furthermore, the gene expression of NOS may be of significance in some glaucoma patients. Logan et al.61 found in their study a statistical significant difference in the distribution of allele frequencies of a specific NOS gene isoform, between subjects with glaucoma that had a history of migraine and control subjects. Other studies on the NOS-mediated L-arginine-NO pathway in eyes of patients with POAG suggest that the pathway is genetically defective.31,62

Altered endothelial vasoreactivity may be a determinant in the development and progression of POAG. However, the specific involvement of endothelial mediators such as ET-1, and NOS in the autoregulatory pathophysiology of POAG has yet to be completely elucidated. Nonetheless, it appears endothelial dysfunction, either primary or secondary to vascular diseases, contributes to POAG pathology.