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Excerpt:
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 (). 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) () ().
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 (). In glaucomatous optic nerves (from humans and animals), researchers have observed more astrocyte proliferation and GFAP (a stress protein) when ET-1 is elevated ().
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 (). 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 (). 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 (). 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,
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