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Endothelin pathway peptides and optic nerve head ischemia in glaucoma · Glaucoma, Vision & Longevity: Supplements & Science

• 0:00
  SPEAKER_00: Endothelin-1 and glaucoma, blood flow, astrocytes, and therapy.
• 0:04
  SPEAKER_00: Endothelin ET1 is a very strong vasoconstrictor, makes blood vessels tighten, found naturally in the body.
• 0:11
  SPEAKER_00: In the eye, ET1 levels and signaling have been linked to damage in glaucoma, a disease of the optic nerve.
• 0:18
  SPEAKER_00: Glaucoma often involves high intraocular pressure, IOP, but other factors, especially reduced blood flow and oxygen, ischemia, at the optic nerve head, can contribute.
• 0:28
  SPEAKER_00: ET1 can narrow small blood vessels around the optic nerve and in the retina, leading to poor oxygen supply.
• 0:34
  SPEAKER_00: It also affects astrocytes, the support cells of the optic nerve, which can become overactive when stressed.
• 0:41
  SPEAKER_00: In this article, we explain how ET1 and its receptors, called ETA and ETB, are involved in glaucoma, how ET1 interacts with nitric oxide, a blood vessel relaxer, evidence that ET1 levels are higher in glaucoma patients, and finally how blocking ET1 receptors might help protect the eye, along with the challenges of such treatments.
• 1:02
  SPEAKER_00: How ET1 affects eye blood flow.
• 1:05
  SPEAKER_00: ET1 is produced by many eye tissues, retina, ciliary body, trabecular meshwork, etc.
• 1:11
  SPEAKER_00: It normally helps regulate blood flow and aqueous humor outflow.
• 1:15
  SPEAKER_00: However, high ET1 causes excessive vasoconstriction.
• 1:19
  SPEAKER_00: For example, human lab studies found that injecting ET1 into the eye rapidly decreases blood flow in the retina and optic nerve head.
• 1:27
  SPEAKER_00: Blood vessel narrowing leads to local ischemia, low oxygen, which can injure retinal ganglion cell RGC axons.
• 1:34
  SPEAKER_00: ET1 even has a direct toxic effect.
• 1:36
  SPEAKER_00: It can trigger RGCs to undergo apoptosis cell death.
• 1:40
  SPEAKER_00: Astrocytes, star-shaped glial cells in the optic nerve, also respond to ET1.
• 1:45
  SPEAKER_00: When ET1 is high, astrocytes can multiply and change shape, a process called astrogliosis.
• 1:52
  SPEAKER_00: This reactive gliosis can further harm the optic nerve environment.
• 1:55
  SPEAKER_00: In lab cultures, ET1 causes optic nerve astrocytes to proliferate, and this effect is blocked by either ETA or ETB receptor inhibitors.
• 2:04
  SPEAKER_00: In glaucomatous optic nerves, from humans and animals, researchers have observed more astrocyte proliferation in GFAP, a stress protein, when ET1 is elevated.
• 2:15
  SPEAKER_00: Nitric oxide and ET1, balancing vessel tone, in healthy eyes, nitric oxide NO and ET1 balance each other.
• 2:22
  SPEAKER_00: NO is a vasodilator, it widens vessels, whereas ET1 constricts them.
• 2:27
  SPEAKER_00: Endothelial cells lining blood vessels release NO under normal conditions, relaxing the vessel walls.
• 2:34
  SPEAKER_00: Any disturbance in this balance, for example, too much ET1 or too little NO, can impair blood flow.
• 2:40
  SPEAKER_00: In the human ophthalmic eye artery, experiments showed that blocking NO causes vessels to constrict and that adding ET1 causes strong constriction.
• 2:48
  SPEAKER_00: Thus ET1's vasoconstriction can overcome NO's dilating effect.
• 2:53
  SPEAKER_00: Indeed, in glaucoma, impaired NO production, often due to endothelial dysfunction, is thought to worsen ET1-induced ischemia.
• 3:01
  SPEAKER_00: In some studies, giving ET1 to people or animals reduced NO-mediated blood flow significantly, and an ETA blocker, like BQ123, could prevent that reduction.
• 3:12
  SPEAKER_00: This crosstalk means that high ET1 disrupts the normal NO-driven relaxation, promoting a harmful cycle of poor blood supply.
• 3:20
  SPEAKER_00: ET1 receptors, ETA and ETB signaling.
• 3:23
  SPEAKER_00: ET1 works by binding two main receptors on cells, ETA, ETA, and ETB, which are on blood vessels and many eye cells, including neurons, glia, and trabecular meshwork cells.
• 3:34
  SPEAKER_00: ETA is found mostly on vascular smooth muscle cells, and its activation strongly causes contraction of vessels.
• 3:41
  SPEAKER_00: ETB is on both smooth muscle and endothelial cells.
• 3:44
  SPEAKER_00: It can also cause constriction, like ETA, but in endothelium it stimulates NO release and ET1 clearance.
• 3:50
  SPEAKER_00: ETA receptor, ETA.
• 3:52
  SPEAKER_00: When ET1 binds ETA on vascular smooth muscle or trabecular meshwork cells, it causes contraction.
• 3:58
  SPEAKER_00: In the eye's drainage system, trabecular meshwork, ETA-mediated contraction tightens the meshwork, raising IOP.
• 4:06
  SPEAKER_00: Animal studies show that most of ET1's effect on increasing IOP goes through ETA.
• 4:11
  SPEAKER_00: For example, adding ET1 to the anterior chamber raises IOP unless an ETA blocker is given.
• 4:17
  SPEAKER_00: In cultured bovine trabecular meshwork, ET1-induced contraction was almost completely stopped by the ETA inhibitor BQ123, while blocking ETB with BQ788 did not affect the contraction.
• 4:30
  SPEAKER_00: Likewise in rabbits, artificially raising ET1 caused ocular hypertension, high IOP, which was prevented by an ETA antagonist.
• 4:38
  SPEAKER_00: These findings mean ETA drives the outflow blockage and IOP rise from ET1.
• 4:43
  SPEAKER_00: Blocking ETA may therefore lower IOP and improve perfusion.
• 4:47
  SPEAKER_00: ETB receptor, ET, ETB has a more complex role.
• 4:51
  SPEAKER_00: In blood vessels, it can help clear ET1 and induce local NO release, which dilates vessels.
• 4:56
  SPEAKER_00: However, in retinal ganglion cells and optic nerve astrocytes, ETB actually can promote cell stress.
• 5:02
  SPEAKER_00: Lab studies found that ET1 triggered RGC apoptosis via ETB, not ETA.
• 5:07
  SPEAKER_00: RGCs showed ET1-induced death that was reduced in animals lacking ETB receptors, and applying an ETB blocker, BQ788, protected cultured RGCs from ET1-driven apoptosis.
• 5:18
  SPEAKER_00: ET1 also disrupted fast axonal transport in RGC axons via ETB.
• 5:23
  SPEAKER_00: Thus, ETB seems to mediate ET1's direct neurotoxic effects.
• 5:27
  SPEAKER_00: ETB on astrocytes also contributes to gliosis.
• 5:30
  SPEAKER_00: ET1 causes astrocytes to proliferate via combined ETA-ETB signaling, and a mixed antagonist can stop it.
• 5:37
  SPEAKER_00: ETA-ETB and nitric oxide crosstalk, ET1's vasoconstriction via ETB can suppress NO pathways.
• 5:44
  SPEAKER_00: High ET1 levels can reduce the activity of nitric oxide synthase, lowering NO production and removing vascular relaxation.
• 5:51
  SPEAKER_00: In atherosclerosis models, blocking ETA restored endothelial NO release.
• 5:56
  SPEAKER_00: Although direct studies in glaucoma are limited, in general, vascular beds ET1 reduces NO, and vice versa.
• 6:03
  SPEAKER_00: In the human eye, as noted, ET1 injection caused vessel constriction that could be blocked by ETA antagonists.
• 6:10
  SPEAKER_00: Conversely, NO donors can counter ET1.
• 6:12
  SPEAKER_00: In eye trabecular cells, NO donors relax the cells and reversed ET1 contraction.
• 6:18
  SPEAKER_00: Overall, ET1 and NO act as opposing regulators of ocular blood flow.
• 6:23
  SPEAKER_00: Too much ET1 tips the balance towards constriction and ischemia.
• 6:27
  SPEAKER_00: Elevated endothylin 1 in glaucoma patients.
• 6:30
  SPEAKER_00: Many studies have measured ET1 levels in glaucoma patients' aqueous humor, the clear fluid in the front of the eye, and in blood.
• 6:37
  SPEAKER_00: The evidence shows higher ET1 in glaucoma.
• 6:41
  SPEAKER_00: In a recent large study, aqueous humor ET1 averaged about 7.8 PDS per milliliter in primary open-angle glaucoma patients and 6.1 Premolet in normal tension glaucoma NTG versus only 4.0 P gram per milliliter in non-glaucoma controls.
• 6:57
  SPEAKER_00: The raise in POEG was statistically significant.
• 7:00
  SPEAKER_00: Meta-analyses similarly find elevated plasma ET1 levels in NTG and POEG compared to healthy controls.
• 7:06
  SPEAKER_00: For example, one analysis of multiple studies reported that NTG patients had an average of 0.60 P gram milliliter higher plasma ET1 than controls, and POA patients by 0.63 P gram milliliter higher.
• 7:18
  SPEAKER_00: Another systematic review compiled data on over 1,500 glaucoma patients and also found significantly higher ET1 in both blood and ocular fluid of glaucoma cases compared to normal eyes.
• 7:30
  SPEAKER_00: However, not all studies agree perfectly.
• 7:33
  SPEAKER_00: Some older work found no plasma difference, possibly due to small samples or patient variations.
• 7:40
  SPEAKER_00: But overall, the trend is clear.
• 7:42
  SPEAKER_00: ET1 is elevated in glaucoma, at least in the eye, and often in blood as well.
• 7:47
  SPEAKER_00: These higher ET1 levels could reflect systemic vascular dysfunction seen in glaucoma patients, especially those with vascular dysregulation or migraines.
• 7:57
  SPEAKER_00: Importantly, increased ET1 in the eye could reduce optic nerve perfusion and trigger astrocyte activation right where glaucoma damage happens.
• 8:05
  SPEAKER_00: Endothelin receptor antagonists.
• 8:08
  SPEAKER_00: Lab models and effects.
• 8:10
  SPEAKER_00: Because ET1 seems harmful in glaucoma, researchers have tested drugs that block ETA and ETB receptors in animal models.
• 8:18
  SPEAKER_00: These endothelin receptor antagonists can be peptide drugs like BQ123, BQ788, or non-peptide small molecules like Boccentin, ambricent, and massetent.
• 8:28
  SPEAKER_00: Peptide antagonists, e.g.
• 8:30
  SPEAKER_00: BQ123, BQ788, these were the first generation and are often used experimentally.
• 8:36
  SPEAKER_00: BQ123 is selective for ETA and BQ788 for ETB.
• 8:40
  SPEAKER_00: In lab glaucoma models, they confirm the roles above BQ123, ETA blocker, prevented ET1-induced IOP spikes, and stopped ET1-caused trabecular meshwork contraction.
• 8:52
  SPEAKER_00: BQ788, ETB blocker, had little effect on IOP in those models, consistent with ETB's smaller role in outflow, but did reduce RGC death from ET1 in cell studies.
• 9:04
  SPEAKER_00: One study found that applying BQ123 systemically blocked ET1's reduction of optic nerve blood flow in humans, showing ET1 was the cause of that constriction.
• 9:14
  SPEAKER_00: Non-peptide antagonists, e.g., bosentin, masetentin, ambricentin, these drugs were developed for pulmonary hypertension and can be taken by mouth or injection.
• 9:24
  SPEAKER_00: In eye studies, they show promise.
• 9:27
  SPEAKER_00: For example, MACTENTAN, a dual ETA-ETB blocker, was given orally to rats with glaucoma, high IOP model.
• 9:34
  SPEAKER_00: It significantly protected retinal ganglion cells and their axons, even though it did not further lower IOP.
• 9:40
  SPEAKER_00: This suggests a direct neuroprotective effect separate from pressure.
• 9:44
  SPEAKER_00: Similarly, bosintan, another dual blocker, prevented optic nerve damage when given systemically in mouse glaucoma models.
• 9:52
  SPEAKER_00: In diabetic rats, topical bosintan eye drops actually reached the retina, likely via the sclera, and prevented glial activation and cell death.
• 10:01
  SPEAKER_00: These results hint that non-peptide blockers can access the eye and help.
• 10:05
  SPEAKER_00: In summary, in preclinical models, ETA selective antagonists have been shown to lower IOP responses to ET1 and reduce pressure-induced damage, while ETB selective or dual antagonists help prevent ET1's direct neurotoxicity, protection of RGCs.
• 10:22
  SPEAKER_00: Dual blockade tended to be the most protective overall.
• 10:26
  SPEAKER_00: Therapeutic prospects and challenges.
• 10:28
  SPEAKER_00: Targeting ET1 is attractive as a glaucoma therapy because it could help beyond just lowering IOP.
• 10:34
  SPEAKER_00: By improving blood flow in the optic nerve head and calming astrocytes, ET receptor blockers may slow neurodegeneration.
• 10:41
  SPEAKER_00: Indeed, as noted, systemic bosintan or masotentan was neuroprotective in animal glaucoma models.
• 10:48
  SPEAKER_00: If these findings translate, adding an ET receptor antagonist could protect vision even when pressure-lowering drugs are maxed out.
• 10:56
  SPEAKER_00: However, there are challenges.
• 10:58
  SPEAKER_00: Systemic side effects of endothellin blockers are significant.
• 11:01
  SPEAKER_00: Drugs like bosintan and ambroscentin can cause systemic hypotension, liver enzyme elevations, fluid retention, headache, and especially severe birth defects if used in pregnancy.
• 11:13
  SPEAKER_00: These arise because ET1 is important in blood vessels throughout the body.
• 11:17
  SPEAKER_00: For glaucoma patients who may be older or have cardiovascular issues, such side effects are serious.
• 11:24
  SPEAKER_00: For example, dose-dependent liver toxicity limits how much a patient can take.
• 11:29
  SPEAKER_00: To reduce systemic risks, researchers are exploring targeted ocular delivery.
• 11:34
  SPEAKER_00: Ideally, an ET blocker could be given as an eye drop or implant that stays mostly in the eye.
• 11:40
  SPEAKER_00: There are early signs this may work.
• 11:42
  SPEAKER_00: In a mouse model of diabetic eye disease, daily eye drops of bosintan penetrated the eye via the sclera and protected retinal cells, suggesting even large molecules can be delivered.
• 11:53
  SPEAKER_00: Other strategies include slow-release ocular implants or gene therapy to locally knock down ET1.
• 12:00
  SPEAKER_00: If an eye-specific ET antagonist can be made, it might avoid blood pressure effects, but still improve optic nerve perfusion and reduce gliosis.
• 12:09
  SPEAKER_00: Conclusion.
• 12:10
  SPEAKER_00: In summary, endothelin-1 is a powerful peptide that can worsen glaucoma by constricting blood vessels in the eye and activating astrocytes.
• 12:19
  SPEAKER_00: High ET1 levels have been found in the eyes and blood of glaucoma patients.
• 12:24
  SPEAKER_00: ET1 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.
• 12:35
  SPEAKER_00: Although more research is needed, blocking this pathway offers a promising avenue.
• 12:40
  SPEAKER_00: In animal studies, endothylin receptor antagonists improve blood flow and protected retinal neurons independently of lowering IOP.
• 12:48
  SPEAKER_00: Any future therapy must carefully avoid systemic effects.
• 12:52
  SPEAKER_00: New drug designs and ocular delivery methods are under study so that the treatment specifically acts in the eye.
• 12:59
  SPEAKER_00: 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.
• 13:13
  SPEAKER_00: Continued research may turn this pathway into a practical neuroprotective therapy for glaucoma patients.
• 13:20
  SPEAKER_00: All links to sources are available in the text version of this article.
• 13:23
  SPEAKER_00: You can find the full article at VisualFieldTest.com.
• 13:28
  SPEAKER_00: Thanks for listening.
• 13:29
  SPEAKER_00: To check your visual field, click the link at the bottom of this article or visit visualfieldtest.com.