Endothelin-1 and Glaucoma: Blood Flow, Astrocytes, and Therapy
Endothelin-1 (ET-1) is a very strong vasoconstrictor (makes blood vessels tighten) found naturally in the body. In the eye, ET-1 levels and signaling have been linked to damage in glaucoma, a disease of the optic nerve. Glaucoma often involves high intraocular pressure (IOP), but other factors – especially reduced blood flow and oxygen (ischemia) at the optic nerve head – can contribute. ET-1 can narrow small blood vessels around the optic nerve and in the retina, leading to poor oxygen supply. It also affects astrocytes, the support cells of the optic nerve, which can become overactive when stressed. In this article, we explain how ET-1 and its receptors (called ETA and ETB) are involved in glaucoma, how ET-1 interacts with nitric oxide (a blood‐vessel relaxer), evidence that ET-1 levels are higher in glaucoma patients, and finally how blocking ET-1 receptors might help protect the eye (along with the challenges of such treatments).
How ET-1 Affects Eye Blood Flow
ET-1 is produced by many eye tissues (retina, ciliary body, trabecular meshwork, etc.). It normally helps regulate blood flow and aqueous humor outflow. However, high ET-1 causes excessive vasoconstriction. For example, human lab studies found that injecting ET-1 into the eye rapidly decreases blood flow in the retina and optic nerve head (pmc.ncbi.nlm.nih.gov). Blood vessel narrowing leads to local ischemia (low oxygen), which can injure retinal ganglion cell (RGC) axons. ET-1 even has a direct toxic effect: it can trigger RGCs to undergo apoptosis (cell death) (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).
Astrocytes – star-shaped glial cells in the optic nerve – also respond to ET-1. When ET-1 is high, astrocytes can multiply and change shape (a process called astrogliosis). This reactive gliosis can further harm the optic nerve environment. In lab cultures, ET-1 causes optic nerve astrocytes to proliferate, and this effect is blocked by either ETA or ETB receptor inhibitors (pmc.ncbi.nlm.nih.gov). In glaucomatous optic nerves (from humans and animals), researchers have observed more astrocyte proliferation and GFAP (a stress protein) when ET-1 is elevated (pmc.ncbi.nlm.nih.gov).
Nitric Oxide and ET-1: Balancing Vessel Tone
In healthy eyes, nitric oxide (NO) and ET-1 balance each other. NO is a vasodilator (it widens vessels), whereas ET-1 constricts them. Endothelial cells lining blood vessels release NO under normal conditions, relaxing the vessel walls (pubmed.ncbi.nlm.nih.gov). Any disturbance in this balance – for example, too much ET-1 or too little NO – can impair blood flow. In the human ophthalmic (eye) artery, experiments showed that blocking NO causes vessels to constrict and that adding ET-1 causes strong constriction (pubmed.ncbi.nlm.nih.gov). Thus, ET-1’s vasoconstriction can overcome NO’s dilating effect. Indeed, in glaucoma, impaired NO production (often due to endothelial dysfunction) is thought to worsen ET-1–induced ischemia. In some studies, giving ET-1 to people or animals reduced NO-mediated blood flow significantly, and an ETA-blocker (like BQ-123) could prevent that reduction (pmc.ncbi.nlm.nih.gov). This cross-talk means that high ET-1 disrupts the normal NO-driven relaxation, promoting a harmful cycle of poor blood supply.
ET-1 Receptors: ETA and ETB Signaling
ET-1 works by binding two main receptors on cells, ETA (ET_A) and ETB (ET_B), which are on blood vessels and many eye cells (including neurons, glia, and trabecular meshwork cells). ETA is found mostly on vascular smooth muscle cells, and its activation strongly causes contraction of vessels. ETB is on both smooth muscle and endothelial cells; it can also cause constriction (like ETA) but in endothelium it stimulates NO release and ET-1 clearance.
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ETA receptor (ET_A): When ET-1 binds ETA on vascular smooth muscle or trabecular meshwork cells, it causes contraction. In the eye’s drainage system (trabecular meshwork), ETA-mediated contraction tightens the meshwork, raising IOP (pmc.ncbi.nlm.nih.gov). Animal studies show that most of ET-1’s effect on increasing IOP goes through ETA: for example, adding ET-1 to the anterior chamber raises IOP unless an ETA blocker is given. In cultured bovine trabecular meshwork, ET-1–induced contraction was almost completely stopped by the ETA inhibitor BQ-123, while blocking ETB (with BQ-788) did not affect the contraction (pmc.ncbi.nlm.nih.gov). Likewise in rabbits, artificially raising ET-1 caused ocular hypertension (high IOP), which was prevented by an ETA antagonist (pmc.ncbi.nlm.nih.gov). These findings mean ETA drives the outflow blockage and IOP rise from ET-1. Blocking ETA may therefore lower IOP and improve perfusion.
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ETB receptor (ET_B): ETB has a more complex role. In blood vessels it can help clear ET-1 and induce local NO release (which dilates vessels). However, in retinal ganglion cells and optic nerve astrocytes, ETB actually can promote cell stress. Lab studies found that ET-1 triggered RGC apoptosis via ETB, not ETA (pmc.ncbi.nlm.nih.gov). RGCs showed ET-1–induced death that was reduced in animals lacking ETB receptors, and applying an ETB blocker (BQ-788) protected cultured RGCs from ET-1–driven apoptosis (pmc.ncbi.nlm.nih.gov). ET-1 also disrupted fast axonal transport in RGC axons via ETB (pmc.ncbi.nlm.nih.gov). Thus ETB seems to mediate ET-1’s direct neurotoxic effects. ETB on astrocytes also contributes to gliosis: ET-1 causes astrocytes to proliferate via combined ETA/ETB signaling, and a mixed antagonist can stop it (pmc.ncbi.nlm.nih.gov).
ETA/ETB and Nitric Oxide Cross-Talk
ET-1’s vasoconstriction via ETA/ETB can suppress NO pathways. High ET-1 levels can reduce the activity of nitric oxide synthase, lowering NO production and removing vascular relaxation. In atherosclerosis models, blocking ETA restored endothelial NO release (pmc.ncbi.nlm.nih.gov). Although direct studies in glaucoma are limited, in general vascular beds ET-1 reduces NO, and vice versa. In the human eye, as noted, ET-1 injection caused vessel constriction that could be blocked by ETA antagonists (pmc.ncbi.nlm.nih.gov). Conversely, NO donors can counter ET-1 – in eye trabecular cells, NO donors relaxed the cells and reversed ET-1 contraction (pmc.ncbi.nlm.nih.gov). Overall, ET-1 and NO act as opposing regulators of ocular blood flow: too much ET-1 tips the balance towards constriction and ischemia (pubmed.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).
Elevated Endothelin-1 in Glaucoma Patients
Many studies have measured ET-1 levels in glaucoma patients’ aqueous humor (the clear fluid in the front of the eye) and in blood. The evidence shows higher ET-1 in glaucoma. In a recent large study, aqueous humor ET-1 averaged about 7.8 pg/mL in primary open-angle glaucoma (POAG) patients and 6.1 pg/mL in normal-tension glaucoma (NTG), versus only 4.0 pg/mL in non-glaucoma controls (pmc.ncbi.nlm.nih.gov). The raise in POAG was statistically significant. Meta-analyses similarly find elevated plasma ET-1 levels in NTG and POAG compared to healthy controls (pmc.ncbi.nlm.nih.gov). For example, one analysis of multiple studies reported that NTG patients had an average of ~0.60 pg/mL higher plasma ET-1 than controls, and POAG patients ~0.63 pg/mL higher (pmc.ncbi.nlm.nih.gov). Another systematic review compiled data on over 1500 glaucoma patients and also found significantly higher ET-1 in both blood and ocular fluid of glaucoma cases compared to normal eyes (pmc.ncbi.nlm.nih.gov).
However, not all studies agree perfectly. Some older work found no plasma difference, possibly due to small samples or patient variations (pmc.ncbi.nlm.nih.gov). But overall the trend is clear: ET-1 is elevated in glaucoma, at least in the eye (and often in blood as well) (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). These higher ET-1 levels could reflect systemic vascular dysfunction seen in glaucoma patients, especially those with vascular dysregulation or migraines. Importantly, increased ET-1 in the eye could reduce optic nerve perfusion and trigger astrocyte activation right where glaucoma damage happens.
Endothelin Receptor Antagonists: Lab Models and Effects
Because ET-1 seems harmful in glaucoma, researchers have tested drugs that block ETA and ETB receptors in animal models. These endothelin receptor antagonists can be peptide drugs (like BQ-123, BQ-788) or non-peptide small molecules (like bosentan, ambrisentan, macitentan).
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Peptide antagonists (e.g. BQ-123, BQ-788): These were the first generation and are often used experimentally. BQ-123 is selective for ETA, and BQ-788 for ETB. In lab glaucoma models, they confirm the roles above: BQ-123 (ETA blocker) prevented ET-1–induced IOP spikes (pmc.ncbi.nlm.nih.gov) and stopped ET-1–caused trabecular meshwork contraction (pmc.ncbi.nlm.nih.gov). BQ-788 (ETB blocker) had little effect on IOP in those models (consistent with ETB’s smaller role in outflow) but did reduce RGC death from ET-1 in cell studies (pmc.ncbi.nlm.nih.gov). One study found that applying BQ-123 systemically blocked ET-1’s reduction of optic nerve blood flow in humans, showing ET-1 was the cause of that constriction (pmc.ncbi.nlm.nih.gov).
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Non-peptide antagonists (e.g. bosentan, macitentan, ambrisentan): These drugs were developed for pulmonary hypertension and can be taken by mouth or injection. In eye studies, they show promise. For example, macitentan, a dual ETA/ETB blocker, was given orally to rats with glaucoma (high IOP model). It significantly protected retinal ganglion cells and their axons even though it did not further lower IOP (pmc.ncbi.nlm.nih.gov). This suggests a direct neuroprotective effect separate from pressure. Similarly, bosentan (another dual blocker) prevented optic nerve damage when given systemically in mouse glaucoma models (pmc.ncbi.nlm.nih.gov). In diabetic rats, topical bosentan eye-drops actually reached the retina (likely via the sclera) and prevented glial activation and cell death (pmc.ncbi.nlm.nih.gov). These results hint that non-peptide blockers can access the eye and help.
In summary, in preclinical models ETA-selective antagonists have been shown to lower IOP responses to ET-1 and reduce pressure-induced damage (pmc.ncbi.nlm.nih.gov), while ETB-selective or dual antagonists help prevent ET-1’s direct neurotoxicity (protection of RGCs) (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Dual blockade tended to be the most protective overall.
Therapeutic Prospects and Challenges
Targeting ET-1 is attractive as a glaucoma therapy because it could help beyond just lowering IOP. By improving blood flow in the optic nerve head and calming astrocytes, ET-receptor blockers may slow neurodegeneration. Indeed, as noted, systemic bosentan or macitentan was neuroprotective in animal glaucoma models (pmc.ncbi.nlm.nih.gov). If these findings translate, adding an ET-receptor antagonist could protect vision even when pressure-lowering drugs are maxed out.
However, there are challenges. Systemic side effects of endothelin blockers are significant. Drugs like bosentan and ambrisentan can cause systemic hypotension, liver enzyme elevations, fluid retention, headache, and especially severe birth defects if used in pregnancy (pmc.ncbi.nlm.nih.gov). These arise because ET-1 is important in blood vessels throughout the body. For glaucoma patients (who may be older or have cardiovascular issues), such side effects are serious. For example, dose-dependent liver toxicity limits how much a patient can take (pmc.ncbi.nlm.nih.gov).
To reduce systemic risks, researchers are exploring targeted ocular delivery. Ideally, an ET-blocker could be given as an eye drop or implant that stays mostly in the eye. There are early signs this may work: in a mouse model of diabetic eye disease, daily eye drops of bosentan penetrated the eye via the sclera and protected retinal cells (pmc.ncbi.nlm.nih.gov), suggesting even large molecules can be delivered. Other strategies include slow-release ocular implants or gene therapy to locally knock down ET-1. If an eye-specific ET antagonist can be made, it might avoid blood pressure effects but still improve optic nerve perfusion and reduce gliosis.
Conclusion
In summary, endothelin-1 is a powerful peptide that can worsen glaucoma by constricting blood vessels in the eye and activating astrocytes. High ET-1 levels have been found in the eyes and blood of glaucoma patients (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). ET-1 acts mainly through ETA receptors to raise eye pressure and cut off blood flow, and through ETB receptors to directly harm retinal ganglion cells and provoke gliosis. Although more research is needed, blocking this pathway offers a promising avenue. In animal studies, endothelin receptor antagonists improved blood flow and protected retinal neurons independently of lowering IOP (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).
Any future therapy must carefully avoid systemic effects. New drug designs and ocular delivery methods are under study so that the treatment specifically acts in the eye. If successful, endothelin-blocking drugs – perhaps as eye drops or implantable devices – could complement existing glaucoma treatments by preserving the optic nerve through better blood flow and reduced inflammation. Continued research may turn this pathway into a practical neuroprotective therapy for glaucoma patients.