Hypoxia-related retinal/choroidal vascular disorders: Pathogenesis and mechanism

To the Editor: The retina is one of the most oxygen-consuming tissues in the human body and is particularly sensitive to hypoxia. Hypoxia can result in an imbalance in the expression of vascular growth factors, cytokines, chemokines, and other cell mediators, which may cause leakage of vascular blood and neovascularization, eventually leading to blindness or severe visual impairment. Hypoxia is a pathological risk factor associated with various retinal/choroidal vascular diseases, such as diabetic retinopathy (DR), retinal vein occlusion (RVO), retinopathy of prematurity (ROP), and wet age-related macular degeneration (AMD), which affect people of all ages, including children, working adults, and elderly individuals. The retina is composed of different types of cells, including retinal pigment epithelial (RPE) cells, rod and cone photoreceptor cells, horizontal cells, bipolar cells, amacrine cells, Müller cells, microglia, ganglion cells, pericytes, and endothelial cells, which are arranged in an orderly manner. Close metabolic exchange occurs between these cells, and the outer retina consumes more than 60% of the retina’s oxygen. Glucose is the source of the retina’s normal metabolism and energy requirements, producing energy through two related metabolic pathways: glycolysis in the cytoplasm and oxidative phosphorylation in the mitochondria. The retina is a tissue with a very high demand for glycolysis. Glucose in the retina is oxidized into pyruvate, which can either be converted into lactate or transported to the mitochondria and completely oxidized to produce more adenosine triphosphate.[1] Normally, high lactate levels are associated with a lack of oxygen, but in the retina, high lactate levels can occur even when oxygen and mitochondrial respiration are present.[1] The mature human retina has a dual blood supply system. In the inner retina, the central retinal artery branches into a dense microvascular network with multiple capillary plexuses, which meet metabolic needs. In retinal circulation, there is a relatively large arteriovenous oxygen difference, indicating that a greater amount of oxygen is absorbed and consumed by the retina. Generally, the inner retina is more susceptible to the effects of ischemia when blood flow is impaired. The outer retina, which is composed of the outer plexiform layer, outer nuclear layer, photoreceptors, and RPE, is supplied with blood and oxygen via the high-flow choriocapillaris network. When blood perfusion in the choroidal layer is low, an insufficient oxygen supply results in choroid atrophy and thinning, as well as damage to photoreceptor cells. Additionally, the choriocapillaris layer provides an important source of oxygen and nutrients to the macula, which has the strongest energy metabolism in the retina and is especially sensitive to hypoxia. The pathological mechanisms responsible for retinal and choroidal vascular damage are complicated. Oxidative stress reportedly plays a crucial role in this process. The imbalance between oxygen-free radical production and elimination under hypoxic conditions leads to the accumulation of reactive oxygen species (ROS), which are chemically reactive oxygen-containing free radicals that include superoxide anions, hydrogen peroxide, and hydroxyl free radicals. The retina is extremely vulnerable to ROS-induced oxidative damage, as it is not only one of the most oxygen-hungry tissues in the body but also directly exposed to a large amount of light and susceptible to photooxidative damage. In patients with DR, a high level of ROS in the diabetic retina directly damages mitochondrial DNA, resulting in mitochondrial dysfunction, or triggers cytochrome c release, disrupts the mitochondrial membrane potential, and promotes retinal capillary cell apoptosis.[2] Oxidative stress not only causes pathological changes in the structure and function of the retinal microvascular system but also promotes the production of inflammatory mediators and cell damage, resulting in retinal neurovascular dysfunction and accelerating the progression of DR. Oxidative stress also influences the progression of RVO by altering blood status. The prothrombotic state is closely related to oxidative damage, which can increase platelet activation, tissue factor activity, and anticoagulant dysfunction, triggering vascular inflammation and thrombosis. In turn, when retinal venous blood flow is partially or completely blocked, retinal hypoxia induces the production of a large amount of ROS, which causes peroxidation of erythrocyte membrane lipids, alters the structure and function of erythrocyte membranes, and increases the risk of thrombosis and the incidence of RVO. ROP is a typical ocular disease of premature infants induced by oxidative stress. The occurrence of ROP is related to hypoxia and redox signaling pathways. Hypoxic conditions increase retinal ROS production and then promote hypoxia-inducible factor (HIF)-1α expression. This factor plays a role in transcriptional regulation and upregulates the expression of a variety of oxygen-sensing genes and angiogenic genes, such as vascular endothelial growth factor (VEGF), erythropoietin, insulin-like growth factor-1, and nitric oxide synthase (NOS).[3] Furthermore, several factors contribute to hypoxia in the outer retina, including thinning choroidal capillaries, decreased choroidal perfusion, and increased vitreomacular adhesion, which increase ROS production and VEGF expression, promote the production of harmful free radicals, and ultimately lead to increased permeability of the microvascular endothelium and vascular leakage. Inflammation is a protective response of the body against adverse stimuli and is closely associated with the progression of hypoxic retinal/choroidal vascular damage. HIF-1 plays an important role in this process. Under hypoxic conditions, HIF-1α activates the nuclear factor-kappaB (NF-κB) pathway, which regulates the release of multiple inflammatory mediators. Hypoxia can induce monocyte chemotactic protein-1 expression in the retina, attracting macrophages to the hypoxic area.[4] Tumour necrosis factor-alpha (TNF-α) secretion by hypoxia-activated macrophages or microglia leads to the release of interleukin (IL)-8, VEGF, fibroblast growth factor (FGF), and other inflammatory and angiogenic factors in retinal vascular cells and glial cells.[4] Furthermore, chemokines regulate leukocyte adhesion to hypoxic vascular endothelial cells by increasing the expression of adhesion molecules such as intercellular cell adhesion molecule-1 and vascular cell adhesion molecule-1, thus promoting leukocyte stasis and platelet–endothelial interactions. This results in endothelial damage and destruction of the blood–retinal barrier (BRB), causing retinal ischemia and hypoxia, as well as the growth of new blood vessels. Moreover, the excessive accumulation of inflammatory cells in the retina blocks microcirculation and causes blood congestion, which further exacerbates the imbalance between the oxygen supply and demand in the retina. Disturbed oxygen homeostasis caused by hypoxia promotes uncontrolled angiogenesis, including abnormal vascular structures and vessel locations. Angiogenesis involves the regulation of multiple factors, especially VEGF, FGF, epidermal growth factor, neuropeptidase, platelet-derived growth factor, erythropoietin, and angiogenin. VEGF is regarded as the primary regulator of retinal/choroidal neovascularization (CNV). In patients with DR, retinal hypoxia accelerates the apoptosis of pericytes and endothelial cells and increases the local release of growth factors and cytokines, which act on endothelial cells directly or indirectly, changing the balance of proangiogenic and antiangiogenic factors. The severity and extent of retinal hypoxia also influence the progression of neovascularization in RVO patients. Patients with central RVO (CRVO) have a higher concentration of VEGF in their aqueous humor than patients with branch RVO, and patients with ischemic CRVO have higher levels of VEGF expression than those with non-ischemic CRVO. Notably, VEGF induces the expression of adhesion molecules, leading to leukocyte adhesion and damage to the BRB. The progression of ROP is closely related to the dysregulation of the postnatal development of the retinal vasculature, which is caused by an imbalance in endogenous proangiogenic and antiangiogenic factors. VEGF is the most studied modifiable factor in ROP and is significantly elevated in the vitreous of infants with ROP. Furthermore, changes in proangiogenic factors such as erythropoietin and angiopoietin, as well as antiangiogenic factors such as pigment epithelium-derived factor and VEGF165b, have also been reported.[5] Patients with wet AMD have a lower pulsatile ocular blood flow and pulse amplitude than those with dry AMD.[6] Changes in choroidal blood flow, such as decreased and abnormal perfusion, can easily lead to outer retinal hypoxia and CNV formation. Furthermore, drusen deposition contributes to RPE hypoxia, facilitating CNV development. Although the triggering insults differ between these diseases, hypoxia affects retinal hemodynamics, microcirculation, and retinal capillary vaso-obliteration, eventually leading to pathological neovascularization. Autophagy is a process of lysosome-mediated self-digesting of cellular components that is normally maintained at a basic level; however, under hypoxic conditions, it is activated to degrade accumulated proteins and damaged organelles to improve cell survival. According to recent research, autophagic vesicles accumulate in the retinal neovascular tufts of oxygen-induced retinopathy (OIR) mice. Deletion of endothelial-specific Atg5 in OIR mice reduced pathological neovascularization but did not affect physiological retinal vascularization. Mechanistically, endothelial Atg5 supports mitochondrial function and proangiogenic signaling in the ischemic retina.[7] Notably, the induction (with rapamycin) or inhibition (with chloroquine) of autophagy reduced the neovascular area but did not completely reverse neuronal damage in the ischemic retina. Furthermore, autophagy may contribute to CNV pathology since it is involved in maintaining RPE homeostasis, which is related to BRB integrity and photoreceptor protection. Recently, the RNA demethylase α-ketoglutarate-dependent dioxygenase alkB homolog 5 was shown to affect RPE dysfunction and CNV progression by activating the protein kinase B (PKB/AKT)/mammalian target of rapamycin (mTOR) pathway and inhibiting autophagosome formation.[8] In conclusion, we discuss oxidative stress, inflammation, vascular dysfunction, and autophagy as pathological mechanisms responsible for retinal and choroidal vascular damage. However, the intraocular microenvironment is complex, with intricate interactions between different retinal cells and mechanisms. Further elucidation and investigation of the exact pathogenesis and mechanism of hypoxia and retinal/choroidal vascular disorders are needed. These findings will help in the development of promising approaches for the treatment of hypoxia-related vascular diseases. Funding This work was supported by a grant from the National Natural Science Foundation of China (No. 81970824). Conflicts of interest None.