Endothelin and Glaucoma
Endothelin and Glaucoma
21 amino acids
Endothelin-1, the most potent vasoconstrictor peptide known, is elevated in the aqueous humor of glaucoma patients and directly linked to retinal ganglion cell death.
Rosenthal & Fromm, British Journal of Pharmacology, 2011
Rosenthal & Fromm, British Journal of Pharmacology, 2011
View as imageGlaucoma destroys retinal ganglion cells (RGCs), the neurons that carry visual information from the retina to the brain. Lowering intraocular pressure (IOP) slows the disease but does not stop it in every patient, and a substantial fraction of glaucoma cases occur at statistically normal pressures. This gap between pressure management and vision loss has driven researchers to look beyond IOP at the vascular and neurodegenerative mechanisms that kill RGCs. Endothelin-1 (ET-1), a 21-amino-acid vasoconstrictor peptide produced by vascular endothelial cells, has emerged as a central player in both pathways. ET-1 is elevated in the aqueous humor and plasma of primary open-angle glaucoma (POAG) patients, constricts the blood vessels feeding the optic nerve head, and directly promotes RGC death through receptor-mediated signaling.[1] Blocking endothelin signaling lowers IOP and protects RGCs in animal models, and the first endothelin receptor antagonist designed specifically for the eye (PER-001) has completed phase 1/2a clinical trials with positive results. This article covers the full evidence landscape for endothelin in glaucoma, from basic peptide biology through animal models to therapeutic development. For focused coverage of related subtopics, see our articles on neuroprotective peptides for retinal ganglion cells in glaucoma and peptide approaches to glaucoma.
Key Takeaways
- Endothelin-1 is the most potent vasoconstrictor peptide in the human body and is elevated in aqueous humor and plasma of POAG patients (Rosenthal & Fromm, British Journal of Pharmacology, 2011)
- A single intravitreal injection of ET-1 in rats produces measurable retinal ganglion cell loss within days, establishing a direct causal link between the peptide and neurodegeneration (Lau et al., Experimental Eye Research, 2006)
- Endothelin B receptor knockout rats showed reduced RGC loss and less optic nerve degeneration compared to wild-type controls after IOP elevation (Minton et al., PLoS ONE, 2012)
- PER-001, a first-in-class endothelin receptor antagonist intravitreal implant, improved ocular blood flow and visual function in phase 1/2a trials with six-month dosing
- Elevated IOP increases ET-1 expression in retinal astrocytes and aqueous humor in rat models, creating a feed-forward loop between pressure and vasoconstriction (Prasanna et al., Pharmacological Research, 2005)
- Tirzepatide use was associated with a 50% reduced risk of POAG compared to GLP-1 receptor agonists alone (Hong et al., American Journal of Ophthalmology, 2026)
What Is Endothelin-1?
Endothelin-1 belongs to a family of three peptides (ET-1, ET-2, ET-3) encoded by separate genes. All three are 21-amino-acid peptides with two intramolecular disulfide bonds that create a compact, hairpin-like structure. ET-1 is the dominant isoform in the vasculature and the most potent vasoconstrictor identified in mammals, exceeding angiotensin II in vasoconstrictor potency by approximately 10-fold.
The peptide is synthesized as a 212-amino-acid prepro-endothelin that undergoes two proteolytic processing steps. First, furin-like enzymes cleave the prepropeptide to produce big endothelin-1 (38 amino acids), an inactive intermediate. Second, endothelin-converting enzyme (ECE) cleaves big endothelin-1 to release the mature 21-amino-acid peptide. Both processing enzymes are expressed in the eye, and substance P can stimulate endothelin-1 secretion via endothelin-converting enzyme 1 and reactive oxygen species, linking neuropeptide signaling to endothelin production.[2]
ET-1 acts through two G-protein-coupled receptors: endothelin receptor A (ETA) and endothelin receptor B (ETB). ETA mediates vasoconstriction and cell proliferation, while ETB has a dual role, driving vasodilation and nitric oxide release in endothelial cells but vasoconstriction in smooth muscle cells. Both receptors are expressed in ocular tissues including the trabecular meshwork, ciliary body, retinal vasculature, optic nerve head, and retinal ganglion cells themselves.[1]
Discovery and Significance
Yanagisawa and colleagues identified endothelin-1 in 1988 by isolating it from the supernatant of cultured porcine aortic endothelial cells. The peptide was immediately recognized as the most potent vasoconstrictor then known, capable of sustaining vascular contraction for hours at nanomolar concentrations. Three decades of research have since revealed endothelin's involvement in cardiovascular disease, pulmonary hypertension, kidney disease, cancer, and ocular pathology. In glaucoma specifically, ET-1 gained attention after multiple clinical studies in the 1990s documented elevated concentrations in the aqueous humor and plasma of patients with both high-tension and normal-tension variants of the disease.
The endothelin system's relevance to glaucoma extends beyond simple vasoconstriction. Unlike many vasoactive substances that act transiently, endothelin produces sustained contractile effects lasting minutes to hours. In the confined anatomy of the eye, where the optic nerve head receives blood supply through small posterior ciliary arteries with limited collateral circulation, even moderate vasoconstriction can produce functionally relevant ischemia. The optic nerve head's vascular architecture makes it uniquely vulnerable to endothelin-mediated perfusion deficits.
Endothelin in the Vasoactive Peptide Family
Endothelin belongs to a broader family of vasoactive peptides that regulate blood vessel tone and tissue perfusion. Adrenomedullin, a vasodilatory peptide, acts as a functional counterpart to endothelin, relaxing blood vessels and promoting blood flow. ANP, the atrial natriuretic peptide, also opposes endothelin's vasoconstrictive effects. The balance between these vasoconstrictor and vasodilator peptides determines tissue perfusion, and disruption of this balance in the eye contributes to glaucomatous damage. Adrenomedullin, endothelin, and natriuretic peptides co-circulate in plasma and are simultaneously altered in cardiovascular disease states.[3]
How Endothelin-1 Contributes to Glaucoma
The evidence linking endothelin to glaucoma operates through three interconnected mechanisms: elevated intraocular pressure, reduced ocular blood flow, and direct neurotoxicity to retinal ganglion cells.
Intraocular Pressure
Aqueous humor is produced by the ciliary body and drains primarily through the trabecular meshwork into Schlemm's canal. ET-1 contracts the trabecular meshwork and ciliary muscle through ETA receptor activation, reducing aqueous humor outflow facility and increasing IOP. The contractile effect is dose-dependent and sustained, lasting substantially longer than the effects of other vasoactive agents on the same tissue.
In rat models of experimental glaucoma, elevated IOP itself induces ET-1 expression in retinal astrocytes and increases ET-1 concentrations in aqueous humor, creating a positive feedback loop where pressure begets more vasoconstriction, which begets more pressure.[4] This feed-forward mechanism may explain why glaucoma tends to be progressive and why IOP reduction alone does not always halt disease advancement. The astrocyte-derived ET-1 in this model acts in a paracrine fashion, affecting both local vasculature and the RGCs that astrocytes normally support.
Ocular Blood Flow
ET-1 constricts the posterior ciliary arteries that supply the optic nerve head, reducing blood flow to the region where RGC axons converge and are most metabolically vulnerable. The optic nerve head is a metabolically demanding structure: RGC axons make a sharp 90-degree turn at the lamina cribrosa, are unmyelinated as they cross the retina, and depend on mitochondrial ATP production that requires continuous oxygen delivery. Even brief episodes of vasoconstriction-induced ischemia can initiate cascading damage.
Clinical studies have documented that POAG patients show exaggerated peripheral microvascular vasoconstriction in response to ET-1 compared to healthy controls, and that patients with normal-tension glaucoma have abnormal ET-1 responses to postural changes. Plasma ET-1 levels are elevated in some POAG patients, and aqueous humor ET-1 correlates positively with IOP. A 2024 systematic review and meta-analysis confirmed elevated ET-1 in the aqueous humor across multiple glaucoma subtypes, though plasma levels showed more variability between studies. These vascular abnormalities suggest a systemic endothelin dysregulation in glaucoma, not merely a local ocular phenomenon.[1]
Direct Retinal Ganglion Cell Death
ET-1 does not merely starve RGCs of blood supply. The peptide directly activates ETA and ETB receptors on RGC cell bodies and axons, triggering intracellular cascades that lead to cell death. A single intravitreal injection of ET-1 in rats produces measurable RGC loss and optic nerve degeneration within days, establishing that the peptide is directly neurotoxic to these cells independent of chronic IOP elevation.[5]
The relative contributions of ETA and ETB receptors to RGC death have been parsed using receptor-specific knockout animals. Minton and colleagues demonstrated that ETB receptor knockout rats showed reduced RGC loss and attenuated optic nerve degeneration compared to wild-type controls after experimental IOP elevation for four weeks.[6] IOP elevation increased ETB receptor expression in RGCs, the nerve fiber layer, and inner plexiform layer, suggesting that the disease process amplifies the very receptor that mediates cell death. Separate work has shown that vascular-derived ETA receptors also contribute to ET-induced RGC death, meaning both receptor subtypes participate through distinct pathways.
Chronic ET-1 exposure in rat models produces sustained reduction in retinal blood flow, increased astrocyte activation, elevated oxidative stress markers, and RGC death through necroptosis rather than classical apoptosis. This pattern of cell death is consistent with the ischemic-inflammatory mechanism proposed for glaucomatous neurodegeneration.
The Normal-Tension Glaucoma Connection
Normal-tension glaucoma (NTG) accounts for roughly 30-40% of all POAG cases in Western populations and over 70% in East Asian populations. In NTG, IOP remains within the statistically normal range, yet progressive RGC loss and optic nerve damage still occur. This clinical paradox has long suggested that non-pressure mechanisms drive neurodegeneration in a substantial fraction of glaucoma patients.
Endothelin provides a compelling mechanistic explanation for NTG. Patients with NTG show elevated plasma ET-1 compared to both healthy controls and high-tension glaucoma patients, and they demonstrate exaggerated vasospastic responses to cold exposure and postural changes. The endothelin hypothesis for NTG proposes that systemic endothelin dysregulation, rather than local pressure elevation, drives chronic ischemia at the optic nerve head. Supporting this, NTG patients have higher rates of migraine, Raynaud's phenomenon, and other vasospastic conditions, all of which involve endothelin-mediated vascular dysfunction.
This vascular-endothelin model explains why IOP lowering alone is insufficient in many NTG patients: if the primary insult is endothelin-mediated vasoconstriction rather than mechanical pressure, then addressing the vascular component is necessary for adequate neuroprotection.
Endothelin Receptor Antagonists for Glaucoma
The dual pathology of endothelin in glaucoma, raising IOP and killing RGCs, makes receptor antagonism an attractive therapeutic strategy that could address both the pressure and the neurodegeneration simultaneously.
Preclinical Evidence
In animal models, endothelin receptor antagonists lower IOP, improve ocular blood flow, and reduce RGC loss. Macitentan, a pan-endothelin receptor antagonist approved for pulmonary arterial hypertension, ameliorated ET-mediated vasoconstriction and promoted the survival of retinal ganglion cells in rats with experimentally elevated IOP. Bosentan, another dual ETA/ETB antagonist, showed similar protective effects in earlier studies.
The challenge with systemic endothelin antagonism is that ET-1 plays critical roles throughout the cardiovascular system. Systemic ETB blockade can paradoxically increase blood pressure by eliminating the vasodilatory ETB function in endothelial cells. This has driven the development of locally delivered, eye-specific formulations.
PER-001: The First Ocular Endothelin Antagonist
Perfuse Therapeutics developed PER-001, a first-in-class small molecule endothelin receptor antagonist delivered as an intravitreal implant designed for six-month sustained release. The implant approach bypasses systemic exposure entirely, delivering the drug directly to the posterior segment of the eye where RGC damage occurs.
In a completed phase 1/2a clinical trial, a single intravitreal administration of PER-001 added to existing IOP-lowering therapies increased ocular blood flow and improved both visual function and anatomic structure over 24 weeks. The drug was safe and well-tolerated, validating target engagement and the sustained-release profile. Perfuse announced plans to initiate a pivotal-enabling phase 2b trial, and subsequent phase 2 data in both glaucoma and diabetic retinopathy patients showed continued positive signals.
This is the first clinical program specifically targeting the endothelin pathway in glaucoma, and it represents a shift from pressure-only management to combined neuroprotection and vascular improvement.
Selective vs. Dual Receptor Antagonism
A key pharmacological question is whether blocking ETA alone, ETB alone, or both receptors produces the best therapeutic outcome in the eye. ETA blockade would prevent vasoconstriction and some direct neurotoxicity. ETB blockade would prevent RGC death mediated through the ETB receptor but might also eliminate the beneficial vasodilatory ETB signaling in endothelial cells. Dual blockade (as with bosentan and macitentan) addresses both pathways but risks disrupting the endothelin system's homeostatic functions.
Preclinical data from ETB knockout studies suggests that ETB contributes meaningfully to RGC loss, but the optimal clinical approach remains untested in large trials.[6] PER-001's receptor selectivity profile has not been fully disclosed, but its intravitreal delivery route limits systemic exposure regardless of selectivity, which may make the dual vs. selective question less clinically relevant than it is for systemic endothelin antagonists.
Peptide-Based Delivery Approaches
Beyond traditional small molecule antagonists, peptide-grafted nanogel technology has been explored for sustained endothelin and bradykinin blockade in joint and ocular applications.[7] Engineered peptide-drug conjugates have also achieved sustained RGC protection in animal models through topical eye drop delivery, a modality that would dramatically improve patient compliance compared to intravitreal injections.[8] For a deeper discussion of peptide-based therapeutic strategies for glaucoma, see our article on peptide approaches to glaucoma.
Other Neuroprotective Peptides in Glaucoma Research
Endothelin antagonism is not the only peptide-based strategy under investigation for RGC protection. Several endogenous peptides and synthetic peptide therapeutics have shown neuroprotective effects in glaucoma models.
Neuropeptide Y (NPY) receptor activation preserved inner retinal integrity in a rat glaucoma model through PI3K/Akt signaling, protecting RGCs from pressure-induced death.[9] The mitochondria-targeted antioxidant peptide SS-31 (elamipretide) demonstrated neuroprotection in experimental glaucoma, reducing RGC loss by targeting mitochondrial oxidative stress, a downstream consequence of ET-1-induced ischemia.[10]
The peptide SS-31 (elamipretide) targets a specific vulnerability in ET-1-mediated neurodegeneration. ET-1-induced ischemia disrupts mitochondrial electron transport in RGCs, generating reactive oxygen species that damage cellular components. SS-31 concentrates in the inner mitochondrial membrane, stabilizing cardiolipin and preventing the electron transport chain disruption that follows ischemic insult. In the context of glaucoma, this represents a downstream intervention: rather than blocking ET-1 itself, SS-31 protects RGCs from the consequences of ET-1-mediated blood flow reduction.[10]
An unexpected finding from metabolic peptide research has been the association between incretin-based therapies and reduced glaucoma risk. GLP-1 receptor agonists appear to reduce the risk of developing POAG as a secondary benefit of their metabolic effects.[11] Tirzepatide, the dual GIP/GLP-1 receptor agonist, was associated with a 50% reduced risk of POAG (relative risk 0.50, 95% CI 0.34-0.74) compared to GLP-1 receptor agonists alone in a cohort study of over 200,000 patients.[12] The mechanism may involve improved retinal vascular function, reduced neuroinflammation, or direct neuroprotective effects of incretin signaling on RGCs. Systemic semaglutide provided mild vasoprotective and anti-neuroinflammatory effects in ocular models.[13]
The convergence of metabolic peptide therapies and glaucoma protection represents an emerging field that could complement endothelin-targeted approaches. Where endothelin antagonists address the vasoconstrictor and neurotoxic components of glaucomatous damage, incretin-based therapies may address metabolic and inflammatory components. Whether combining these strategies would produce additive neuroprotection is an open question with substantial therapeutic implications.
For a comprehensive review of neuroprotective peptide strategies in glaucoma, see our article on neuroprotective peptides for retinal ganglion cells.
Endothelin Beyond the Eye
The endothelin system participates in pathophysiology well beyond glaucoma, and understanding these roles provides context for ocular endothelin biology.
Pain signaling. The endothelin A receptor in peripheral nociceptors is essential for persistent mechanical pain, positioning endothelin as a mediator of both vascular and sensory pathology.[14] ETB receptor agonists in the periphery can produce antinociception through endogenous opioid peptide release, demonstrating cross-talk between the endothelin and opioid systems.[15]
Pulmonary hypertension. Endothelin receptor antagonists (bosentan, ambrisentan, macitentan) are established treatments for pulmonary arterial hypertension, where chronic ET-1 elevation drives vascular remodeling. The safety profile of these drugs in cardiovascular disease provides confidence for their adaptation to ocular use. Combination therapy with tadalafil plus endothelin receptor antagonists has shown improved outcomes in connective tissue disease-associated pulmonary hypertension.[16]
Cardiovascular regulation. Endothelin circulates alongside adrenomedullin, natriuretic peptides, and neuropeptide Y as part of the peptide network that maintains cardiovascular homeostasis.[3] Disruption of any one of these systems can cascade through the others, which may explain why systemic vascular dysregulation is a risk factor for normal-tension glaucoma.
Kidney disease. Endothelin contributes to renal vasoconstriction and fibrosis, and endothelin receptor antagonists are under investigation for diabetic kidney disease and chronic kidney disease progression. The kidney and the eye share similar microvascular architecture, and patients with chronic kidney disease have elevated rates of glaucoma, suggesting a shared endothelin-mediated vascular vulnerability across organs.
Cancer. Endothelin signaling promotes tumor angiogenesis and cell survival in several cancer types. While this is mechanistically distant from glaucoma, it demonstrates the breadth of endothelin's biological roles and the pharmaceutical industry's investment in endothelin-modulating compounds. Drugs developed for cardiovascular or oncological indications can potentially be repurposed for ocular use, as demonstrated by macitentan's transition from pulmonary hypertension approval to glaucoma preclinical testing.
Fibrosis. ET-1 promotes extracellular matrix deposition and tissue remodeling in the lung, liver, and heart. In the eye, fibrotic changes in the trabecular meshwork contribute to increased aqueous humor outflow resistance. Whether endothelin-driven fibrosis in the trabecular meshwork represents a separate mechanism from its vasoconstrictor and neurotoxic effects is an active area of investigation.
Evidence Gaps and Open Questions
Several questions remain unresolved in endothelin-glaucoma research. The relative contributions of vascular versus direct neurotoxic mechanisms to RGC death are debated. Some RGC loss in glaucoma models may reflect ischemia from vasoconstriction, some may reflect direct receptor-mediated toxicity, and some may reflect secondary inflammation from astrocyte activation. Separating these pathways in living tissue remains technically challenging.
The relationship between systemic endothelin levels and ocular endothelin levels is inconsistent across studies. Some POAG patients show elevated plasma ET-1, while others show elevation only in aqueous humor. Whether systemic endothelin dysregulation causes ocular disease or whether the eye generates ET-1 independently is unclear, and the answer likely varies between patients and glaucoma subtypes.
Sex differences in endothelin biology are documented in cardiovascular research but understudied in glaucoma. Given that estrogen modulates endothelin production and that post-menopausal women have higher POAG risk, this represents a gap with clinical relevance.
Long-term clinical outcome data for endothelin antagonism in glaucoma is limited. PER-001's phase 1/2a results are promising but reflect 24-week follow-up in a small cohort. Whether sustained endothelin blockade can prevent or reverse RGC loss over years of glaucoma progression is the critical question that phase 2b and phase 3 trials will need to answer.
The interaction between endothelin and other glaucoma risk factors (age, genetics, myopia, corticosteroid use) is poorly characterized. Genome-wide association studies have identified multiple risk loci for glaucoma, but the endothelin system genes (EDN1, EDNRA, EDNRB) have not emerged as primary risk loci in large cohorts. This may indicate that endothelin's role is more environmental or secondary rather than a primary genetic driver, or it may reflect the limitations of current GWAS approaches in capturing dynamic peptide system dysfunction.
Biomarker development for endothelin-driven glaucoma is also in early stages. If aqueous humor ET-1 levels could reliably predict which patients would benefit from endothelin antagonism, treatment could be personalized. Current data shows positive correlation between aqueous ET-1 and IOP, but the variability is high, and obtaining aqueous humor samples requires invasive anterior chamber paracentesis, limiting practical clinical utility.
The Bottom Line
Endothelin-1 drives glaucoma through three converging mechanisms: increasing intraocular pressure, constricting blood supply to the optic nerve head, and directly killing retinal ganglion cells through ETA and ETB receptor signaling. Endothelin receptor antagonists address both the vascular and neurodegenerative components of the disease. PER-001, the first ocular endothelin antagonist to reach clinical trials, showed improved blood flow and visual function in phase 1/2a data, with pivotal trials ahead.