The retinal vascular architecture is organized into two principal systems: the inner retinal circulation, derived from the central retinal artery and serving the inner retinal layers (ganglion, inner plexiform and nuclear layers), and the outer retina, which is avascular and relies on diffusion from the choroidal circulation and the retinal pigment epithelium. Because the outer retina is not directly vascularized, it is especially susceptible to hypoxia when the choroidal supply is compromised or when inner retinal swelling impinges on diffusion (13).

Within the inner retina, microcirculatory units comprise arterioles, capillaries, and venules wrapped by pericytes and ensheathed by Müller glial processes. The narrow lumen of capillaries, tight coupling with metabolic demand, and limited collateralization mean that even modest vascular insults can produce localized ischemia. Studies of human donor retinal microcirculation reveal heterogeneity in capillary density and flow reserve, especially in the perifoveal and parafoveal zones, which may contribute to the spatial predilection of ischemic damage in diseases such as central retinal vein occlusion or diabetic retinopathy (14).

Ischemic insult to the retinal microcirculation can result from either vascular occlusion (arterial or venous) or from endothelial dysfunction driven by systemic risk factors (diabetes, hypertension, atherosclerosis). In the case of venous occlusion, elevated venous pressure leads to capillary stasis, hemorrhage, and nonperfusion, while arterial occlusion sharply halts blood supply to downstream capillaries.

Once retinal perfusion is compromised, it initiates a deleterious and self-perpetuating cascade of pathological events. A primary and immediate consequence is tissue hypoxia, which stabilizes hypoxia-inducible factors (HIFs), particularly HIF-1α, that function as master transcriptional regulators of oxygen homeostasis (15). In an initially adaptive effort to salvage compromised tissue, these factors upregulate a suite of genes encoding angiogenic mediators such as Vascular Endothelial Growth Factor (VEGF) and Angiopoietin-2 (ANGPT2), alongside glycolytic enzymes and erythropoietin, thereby promoting vascular perfusion and metabolic reprogramming (15, 16). However, when HIF activation becomes persistent within the retinal environment, this response becomes maladaptive, driving pathological angiogenesis, increasing vascular permeability, and ultimately exacerbating macular edema and ischemic injury (17–19).

Concurrently, the reduced supply of oxygen and nutrients impairs mitochondrial oxidative phosphorylation, leading to a marked generation of reactive oxygen species (ROS) and direct mitochondrial damage. This state of profound oxidative stress inflicts injury upon both the delicate vascular endothelial cells and the neuronal elements of the retina. Over time, ROS perpetuate a destructive cycle by further promoting endothelial dysfunction, causing mitochondrial DNA damage, and ultimately triggering cell death, establishing oxidative stress as a recognized central pathway underlying both microvascular degeneration and neuronal loss in ischemic retinal diseases (20). The resulting endothelial dysfunction critically leads to a loss of tight junction integrity, particularly within the inner blood-retina barrier (BRB). This breach in the retinal vasculature permits the infiltration of plasma proteins and immune cells, significantly exacerbating edema and initiating a robust inflammatory response (21). This process is often amplified in the context of ischemia–reperfusion injury, which further intensifies the inflammatory cascade through mechanisms such as increased leukocyte adhesion mediated by ICAM-1 and selectins, the activation of resident microglia, and the release of pro-inflammatory cytokines including IL-1β, TNF-α, and IL-6. These inflammatory events engage in a vicious cycle with ongoing oxidative stress, collectively contributing to the damage of retinal cells (21).

The culmination of this pathophysiological cascade is the irreversible loss of retinal neurons and the activation of glial cells. Retinal ganglion cells (RGCs), along with other inner retinal neurons like amacrine and bipolar cells, exhibit a high degree of vulnerability to both metabolic stress and excitotoxic injury (22). Prolonged ischemia triggers the excessive release of the neurotransmitter glutamate, leading to calcium overload within neurons and the activation of both apoptotic and inflammatory intracellular cascades (22). This sequence of events is consistently reflected in experimental ischemia–reperfusion models, which demonstrate characteristic findings such as inner retinal thinning, a significant loss of RGCs, a decreased b-wave amplitude on electroretinography indicative of inner retinal dysfunction, and reactive Müller gliosis (23, 24).

Therapeutic strategies in ischemic retinal diseases have evolved to target downstream consequences rather than upstream ischemia. In retinal vein occlusion and diabetic macular edema, intravitreal anti-VEGF agents and corticosteroids are highly effective at reducing vascular permeability and neovascular proliferation. However, these treatments do not directly restore microcirculation, address nonperfusion, or prevent neuronal degeneration in ischemic zones. In fact, anti-VEGF therapies may worsen retinal ischemia or fail to reduce nonperfusion areas (25–27). They often require repeated administration and may not penetrate ischemic or occluded capillaries.

Moreover, in retinal and optic nerve arterial occlusions, therapies aimed at reperfusion (e.g., thrombolysis, hyperbaric oxygen) have shown variable efficacy, mostly limited by narrow time windows and risk of reperfusion injury. Many patients present too late for these interventions. Even when perfusion is restored, microvascular rarefaction, endothelial injury, and capillary dropout may prevent true functional recovery (as evidenced by worsening peripheral ischemia after treatment) (28).

Imaging biomarkers—such as OCT-A quantification of capillary density, non-perfusion maps, or perfusion indices—are increasingly used to stratify disease severity and monitor response (e.g., deep capillary nonperfusion predicting DR progression) (29). However, standardization of these imaging markers across devices and clinical trials is lacking, and predictive thresholds for therapeutic benefit remain undefined (30, 31).

Within this pathophysiological framework, the need to explore novel mechanistic insights and time-sensitive therapeutic strategies for ischemic retinal injury becomes apparent, rather than defining a specific therapeutic window for PGE₁ at this stage. Because PGE₁‘s mechanisms include vasodilation, endothelial protection, antithrombotic effects, anti-inflammatory modulation, and potentially mitochondrial support, it is ideally placed to act upstream of irreversible tissue injury. For maximal efficacy, PGE₁ would need to be delivered early, before capillary dropout and neuronal apoptosis become irreversible, and within a timeframe in which reperfusion remains meaningful. Indeed, a retrospective cohort of CRAO patients receiving PGE₁ within 24 h showed superior visual recovery compared to conventional therapy (10). The urgency is emphasized by estimates that retinal ganglion cells may suffer irreversible injury in as little as 12–15 min after occlusion (32).

PGE₁ is a naturally occurring lipid mediator derived from the cyclooxygenase (COX) pathway that acts primarily through prostanoid (EP) receptors. Although it shares certain pharmacological properties with other prostaglandins, PGE₁ is distinct from PGE₂ in its receptor affinity and downstream signaling, leading to characteristic biological actions such as vasodilation, inhibition of platelet aggregation, and modulation of vascular smooth muscle tone. Increasing attention has recently been directed toward prostanoid signaling within the retina, where different prostaglandin families and receptor subtypes contribute to the regulation of vascular homeostasis, inflammation, and neuronal survival. As highlighted by (33), these mechanisms are relevant to a range of ocular disorders, including diabetic retinopathy, age-related macular degeneration (AMD), retinal vascular occlusions, and uveitis (Table 1).

Recent investigations have explored the potential of PGE₁ to counteract ischemic injury in the retina by enhancing microcirculation and promoting cellular resilience. In a multicenter retrospective study of central retinal artery occlusion (CRAO), early administration of intravenous PGE₁—initiated within 24 h of onset and followed by oral continuation—was associated with improved visual outcomes compared with standard care, suggesting that timely vasodilation and reperfusion of the ischemic retina may be achievable (10). These findings are consistent with earlier reports by (34), who documented rapid restoration of retinal blood flow and improvement in visual acuity after short-term intravenous PGE₁ therapy in CRAO patients. More recently (8) confirmed anatomical and functional recovery following intravenous liposomal PGE₁, further supporting the feasibility of systemic administration in acute retinal ischemia.

Earlier clinical evidence in patients with peripheral vascular disease and diabetes similarly demonstrated that intravenous PGE₁ significantly increases both systolic and diastolic flow velocities in the ophthalmic and central retinal arteries, indicating enhanced ocular perfusion and microcirculatory support (35). Comparable benefits have also been observed in peripheral ischemic conditions: in a large clinical cohort of patients with acute lower-limb ischemia, (36) reported that intravenous liposomal PGE₁ improved tissue perfusion, reduced inflammatory markers, and enhanced post-surgical outcomes, reinforcing the systemic vasoprotective and rheological potential of this agent.

Beyond its hemodynamic actions, PGE₁ exhibits anti-thrombotic and rheological properties through inhibition of platelet aggregation and modulation of blood flow dynamics. Although contemporary retinal-specific studies are limited, systemic investigations have demonstrated its ability to reduce vascular occlusion risk in other contexts, such as the prevention of veno-occlusive disease (37). These findings are consistent with the notion that PGE₁ promotes vascular patency by improving blood rheology and endothelial stability.

Emerging evidence also points to PGE₁‘s role in endothelial protection and anti-inflammatory regulation. In systemic sclerosis, for example, (7) reported that PGE₁ restored the function of endothelial progenitor cells impaired by disease, suggesting a broader endothelial reparative effect. While most research on prostanoid-mediated inflammation has centered on PGE₂ and COX-2–dependent pathways in retinal glia and vasculature, the known endothelial actions of PGE₁—including vasodilation, anti-aggregatory activity, and improved cell survival—imply a potential to mitigate oxidative and inflammatory stress in retinal microvessels (7, 33).

At the molecular level, PGE₁ has been shown to activate antioxidant signaling through the Nrf2/HO-1 axis, reducing neuronal oxidative stress and apoptosis in vitro, as demonstrated by (38). Preclinical studies further support a neuroprotective and potentially mitochondrial-stabilizing role for PGE₁. In animal models of cerebral ischemia, administration of liposomal PGE₁ (lipo-PGE₁) enhanced angiogenesis, promoted neural progenitor cell proliferation, and improved neurological recovery, pointing to reparative and neurogenic effects beyond vascular dilation (39). The clinical observations in CRAO align with these findings, as early treatment was associated with cytoprotective effects and functional visual recovery (10). Although mitochondrial-specific mechanisms have not been fully characterized in retinal tissue, the broader pattern of reduced oxidative injury and inflammation suggests that PGE₁ may sustain neuronal and glial viability under ischemic stress.

Despite its therapeutic promise, PGE₁‘s pharmacological application is limited by its short systemic half-life and metabolic instability. Classic pharmacokinetic studies in animal models have shown that its primary metabolite, 13,14-dihydro-15-keto-PGE₁, has a terminal half-life of approximately 25–34 min, which constrains sustained systemic activity (40). Consequently, most clinical protocols rely on continuous intravenous infusion or repeated daily administration. As described by (10) and confirmed by (9), CRAO treatment typically involves intravenous PGE₁—sometimes followed by oral continuation—to maintain therapeutic exposure. However, systemic delivery, while achieving broad tissue distribution, carries potential risks such as hypotension, headache, and bleeding, reflecting PGE₁’s potent vasodilatory and antiplatelet actions.

Experimental data indicate that effective doses in animal studies (for example, 10 μg/kg/day of lipo-PGE₁ in ischemic stroke models) may not be directly translatable to safe, practical regimens in humans, as such doses could lead to systemic adverse effects if repeated chronically (39). Furthermore, ocular delivery poses additional barriers: the blood–retinal barrier, rapid systemic metabolism, and dilution effects all limit retinal bioavailability. To date, intravitreal or periocular administration of PGE₁ has not been systematically evaluated in modern trials. Novel delivery platforms, including liposomal or sustained-release formulations, may help to overcome these obstacles by prolonging exposure and minimizing systemic side effects.

In terms of safety, no major adverse events were reported in the recent CRAO study using early intravenous PGE₁ (10), yet comprehensive safety assessment requires larger, controlled investigations. The efficacy of PGE₁ also appears to be highly time-dependent—benefits are most evident when administered soon after ischemic onset—underscoring the importance of early diagnosis and appropriate patient selection. Ultimately, while current human evidence remains limited to small case series and retrospective analyses, the convergence of hemodynamic, endothelial, and neuroprotective effects provides a compelling rationale for further randomized clinical trials. Optimizing delivery strategies and establishing validated biomarkers of response will be essential to determine PGE₁‘s definitive place in the management of ischemic and neovascular retinal disorders.

Collectively, these biological and pharmacological properties provide a coherent mechanistic rationale for considering PGE₁ in ischemic retinal conditions. However, mechanistic plausibility alone is insufficient to justify clinical translation. The relevance of these effects must therefore be evaluated within controlled experimental systems and, ultimately, in human disease contexts characterized by distinct temporal, vascular, and cellular constraints.

Recent work in rodent models has clarified the timeline and nature of damage following retinal ischemia/reperfusion (I/R). In Brown-Norway rats subjected to elevated intraocular pressure (IOP) for 60 min followed by reperfusion, optic nerves show early microglial activation (as soon as 12 h), followed by neurofilament degeneration and demyelination by days 3–7 (41). Similarly, rat studies with elevated IOP (140 mmHg for 1 h) demonstrated not only retinal morphological damage, but also optic nerve cell infiltration, microglial activation, and structural degeneration over 21 days (42). These studies establish that both retinal and optic nerve neurons are vulnerable early on and that glial/inflammatory responses precede overt neuronal loss.

While the evidence from cerebral and cardiac models is promising, the preclinical data for PGE₁ in the context of retinal and optic nerve ischemia come with significant limitations. A primary constraint is the sheer lack of well-controlled animal studies directly within these ocular tissues; there is very little specific data on how PGE₁ affects neuronal survival, edema, or oxidative stress in the retina, leaving us to rely heavily on human case series and inferences from other organs.

Furthermore, while studies in the brain and heart clearly show that the timing of administration and the dosage are critical, the optimal therapeutic window and formulation for the retina remain entirely unestablished. This challenge is compounded by the heterogeneity of preclinical models themselves, as different methods of inducing ischemia—such as elevated intraocular pressure versus arterial occlusion—can produce distinct pathological cascades, making it difficult to generalize results. Adding another layer of complexity, many studies focus on anatomical or biochemical endpoints, while robust, long-term assessments of functional recovery, like electroretinography (ERG) or optic nerve conduction, are less common. Finally, a comprehensive understanding of the safety profile is often missing, as detailed reporting of adverse effects, particularly for ocular application, is frequently absent from preclinical work.

Beyond retinal ischemia–reperfusion models, experimental paradigms such as optic nerve crush (ONC) are widely used to study axonal injury, retinal ganglion cell degeneration, and secondary ischemic mechanisms affecting the optic nerve. To date, however, no studies have directly evaluated the effects of PGE₁ in ONC or other optic nerve–specific ischemia models. As such, any potential neuroprotective role of PGE₁ in these contexts remains speculative and warrants targeted experimental investigation.

In sum, preclinical evidence suggests that PGE₁ has promising effects on perfusion, reducing oxidative stress, and improving functional outcomes in non-ocular ischemic models. Retinal/optic nerve specific preclinical work remains limited in scope. To validate translatability, more studies are needed that use retina/optic nerve ischemia models, assess neuronal survival and function, optimize dosing and timing, and document safety in ocular tissues.

Direct preclinical evidence for PGE₁ in retinal or optic nerve ischemia is limited, with only a retrospective human study in central retinal artery occlusion suggesting potential benefits for visual acuity and edema reduction (10). However, robust mechanistic insights from other ischemic tissues support its translatability. In a rat model of ischemic stroke, delayed treatment with lipo-PGE₁ enhanced angiogenesis and neurogenesis, improving functional recovery (39). Similarly, in a rat model of coronary micro-embolization, PGE₁ pre-treatment improved microvascular function, preserved mitochondrial integrity, and mitigated oxidative stress by protecting antioxidant enzymes (43).

Collectively, these findings from the brain and myocardium—tissues that share a vulnerability to ischemia and reperfusion injury with the retina—suggest PGE₁ can modulate perfusion, reduce oxidative damage, and improve outcomes. While direct evidence for neuronal survival in the visual system remains sparse, these parallel mechanisms indicate a strong therapeutic potential.

The short plasma half-life of PGE₁, along with its extensive first-pass pulmonary metabolism, poses a major barrier to durable intraocular exposure following systemic administration (40, 47). Recent advances in ocular pharmacology have opened the possibility of localized, sustained-release delivery systems designed to maintain therapeutic concentrations while minimizing systemic effects. Biodegradable intravitreal implants based on poly(lactic-co-glycolic acid) (PLGA) or lipid matrices can achieve controlled prostaglandin release for weeks to months, a technology already validated for corticosteroids and non-steroidal anti-inflammatory drugs (50). Experimental formulations of prostaglandin-mimetic or vasoprotective nanoparticles have demonstrated targeted endothelial uptake, improved retinal penetration, and enhanced neurovascular protection in rodent ischemia models (51). In particular, PGE₁-containing polymeric nanoparticles have been shown to restore perfusion and functional recovery in experimental vascular ischemia, confirming the feasibility of nanoparticle-based delivery for prostaglandin compounds (52). In parallel, hydrogel-based sustained-release systems are emerging as promising scaffolds for long-term intravitreal delivery (53). Similarly, microneedle-assisted transscleral delivery and subconjunctival depot systems are under investigation to achieve sustained periocular release with minimal invasiveness (54). However, a topical application of PGE₁ directly to the ocular surface would likely provoke undesirable effects, including vasodilation and conjunctival hyperemia (primarily via EP₄ receptors) and inflammatory responses (via EP₁/EP₃ receptors). In contrast, transdermal or subcutaneous routes—already validated for other prostaglandins and for PGE₁ itself in the treatment of erectile dysfunction—could provide a safer and more practical alternative for systemic delivery (55). Transdermal patches and microneedle-based cutaneous systems have been successfully employed for controlled prostaglandin absorption in non-ocular indications, achieving steady plasma concentrations while minimizing peaks that cause hypotension or flushing (56, 57). These results, although extrapolated from systemic applications, support the feasibility of cutaneous delivery as an alternative to intravenous infusion. Such platforms could serve as non-invasive substitutes for intravenous infusion, provided that ocular pharmacokinetics and retinal tissue exposure are rigorously characterized. Future research should focus on optimizing cutaneous sustained-release formulations of PGE₁, which could overcome the pharmacokinetic limitations of systemic infusion and provide a practical, non-invasive approach for chronic neurovascular maintenance therapy.

Given the multifactorial nature of ischemic retinal injury—encompassing vascular constriction, oxidative stress, inflammation, and secondary neuronal degeneration—monotherapy is unlikely to yield maximal benefit. Synergistic combinations of PGE₁ with established pharmacological agents merit systematic evaluation. Anti-VEGF drugs, while highly effective in reducing macular edema (25), do not address the upstream vascular tone and perfusion deficits that PGE₁ may improve (34). Thus, a dual-approach combining PGE₁ with anti-VEGF therapy could theoretically restore perfusion while simultaneously limiting vascular leakage, a hypothesis supported by preclinical evidence showing that PGE₁ exerts endothelial-protective and anti-apoptotic effects under oxidative and hypoxic stress, promoting vascular stability and cell survival through modulation of HIF-1α signaling and attenuation of reactive oxygen–induced injury (58, 59).

The integration of PGE₁ with neuroprotective or anti-inflammatory agents—such as citicoline, brimonidine, or minocycline—also warrants exploration. PGE₁ has been shown to engage EP receptor signaling (notably EP4) and enhance cAMP–PKA activity, a pro-survival axis demonstrated in recent mechanistic work (60). In parallel, PGE₁ exerts endothelial-protective and anti-apoptotic effects in cell and preclinical models (58, 59). Several clinically relevant neuroprotective/anti-inflammatory agents (citicoline, brimonidine, minocycline) have independent evidence of protecting retinal ganglion cells and reducing inflammation/vascular permeability in optic-nerve and retinal ischemia models (61–63). Together, these data justify exploring combined PGE₁ and neuroprotective agent regimens. The cAMP-linked survival signaling downstream of EP₂/EP₄-receptor activation—recently demonstrated as a key neuroprotective mechanism in retinal ganglion cells (64) and reviewed as a major pro-survival pathway in ocular and neural tissues (65)—could plausibly synergize with the anti-apoptotic mechanisms of these agents. However, direct combination studies in ocular models are still needed. Beyond pharmacological synergy, the therapeutic benefit of PGE₁-induced vasodilation can be complemented by multimodal strategies, such as remote ischemic conditioning (RIC) (66) or low-level light therapy (LLLT) (67), both of which are known to directly enhance mitochondrial resilience and function (68, 69).

The clinical success of PGE₁ therapy will ultimately depend on the ability to identify patients most likely to benefit and to monitor perfusion recovery objectively. Recent advances in optical coherence tomography angiography (OCTA) and wide-field perfusion imaging have revolutionized quantitative assessment of retinal microcirculation. Parameters such as vessel-density index, perfused capillary area, and flow-deficit metrics correlate closely with functional recovery in CRAO and RVO (70, 71) Baseline OCTA parameters could therefore serve as predictive biomarkers for responsiveness to vasodilatory therapies like PGE₁, while longitudinal imaging enables dynamic evaluation of treatment efficacy. The development of standardized imaging endpoints will also facilitate inter-study comparability and could bridge mechanistic and clinical research domains.

Emerging modalities such as functional retinal oximetry and laser speckle flowgraphy are likewise expanding insight into microvascular dynamics and oxygen delivery (72, 73). Integration of these quantitative imaging biomarkers into future trials would enable early detection of perfusion changes preceding visual improvement, thereby refining therapeutic windows and patient-selection criteria.

Beyond its hemodynamic effects, PGE₁ exerts downstream influence on mitochondrial integrity, endothelial barrier stability, and neuronal survival. Activation of EP₂/EP₄ receptors engages G_s-mediated cAMP–PKA signaling (74), and cAMP–PKA activity has been shown to preserve mitochondrial supercomplex organization and respiratory efficiency (75); moreover, PGE₁ protects endothelial cells from oxidative injury (58), while EP₂-agonism confers cAMP-dependent neuroprotection in retinal ganglion cells (64), together supporting the proposition that PGE₁ can influence mitochondrial integrity, endothelial barrier stability and neuronal survival via EP-linked cAMP–PKA pathways. This positions PGE₁ as a unique pharmacological bridge between vascular and neuronal protection, aligning with contemporary models of the retina as a neurovascular unit. Translational research should therefore focus on defining molecular markers of PGE₁-induced neurovascular coupling, possibly through combined single-cell transcriptomic and metabolomic profiling in experimental ischemia, to identify cell-type-specific molecular targets and signaling pathways responsive to PGE₁ (76). Such integrative studies may reveal cross-talk with established neurotrophic pathways, including BDNF and NGF signaling, thereby guiding the rational design of next-generation analogues with improved receptor selectivity or resistance to enzymatic degradation. The long-term vision is to evolve PGE₁ therapy from an emergency vasodilator into a chronic neurovascular modulator, administered through sustained-release technologies and guided by precision imaging and molecular diagnostics.