NAD+ modulates mitochondrial vulnerability in MERTK-associated models of retinitis pigmentosa.

Retinopathy, often referring to retinal vascular diseases that include diabetic retinopathy (DR), neovascular age-related macular degeneration (neoAMD), retinopathy of prematurity (ROP), and retinal vein occlusion (RVO), is the leading cause of blindness across all age groups (, ). Proliferative retinopathy (PR) directly involves vascular damages caused by excessive neovascularization and nonproliferative retinopathy (NPR) is usually linked to dysfunction of blood perfusion and vascular leakiness. Under most pathological circumstances, PR and NPR are intertwined two pathological processes that concomitantly contribute to the onset, development, and progression of retinal diseases (, ). One of the common mechanisms underlying various types of retinopathy is tissue hypoxia, which serves as a potent driver of retinal neovascularization and vascular remodeling (). Hypoxia potently induces high expression of vascular endothelial growth factor (VEGF) via the hypoxia-inducible factor 1 (HIF-1)-mediated transcription activation (). VEGF is a key angiogenic factor that displays multifarious vascular functions, including angiogenesis, vascular permeability, vascular remodeling, vascular homeostasis, and endothelial cell survival (, ). VEGF levels in various tissues are tightly regulated and excessive or insufficient VEGF production can lead to onset and progression of various diseases (, ). The VEGF-executed functions are further regulated by two tyrosine kinase receptors, VEGF receptor 1 (VEGFR1) and VEGFR2, displaying often opposing, but complimentary, vascular functions. While VEGFR2 mediates most of VEGF-stimulated functions, VEGFR1 may act as a decoy receptor to further maintain the homeostatic role of VEGF by preventing excessive signaling (). Owing to their predominate roles in retinopathy, the VEGF-VEGFR signaling has become one of the most attractive targets for drug development and effective treatment of various retinal diseases. At the time of this writing, anti-VEGF agents are probably the most commonly used and effective drugs in the clinic for treatment of neoAMD, DR, diabetic macular edema (DME), and RVO. They are often prescribed as the first-line regimen in monotherapeutic settings for treatment of retinal diseases (). Severe COVID-19 manifests respiratory dyspnea that creates pulmonary hypoxia, which would lead to global hypoxia in various tissues and organs (–). In the pulmonary tissue, SARS-CoV-2 infection triggers a robust inflammatory response, angiogenesis, plasma extravasation, and fibrosis (–). These pathological changes further exacerbate tissue hypoxia, which augments VEGF expression (). Since VEGF molecules are synthesized in various spliced isoforms with different molecular weights, the smaller soluble VEGF molecules may function as endocrine hormones by targeting remote tissues and organs (, ). Thus, in each tissue local and circulating VEGFs collectively participate in the COVID-19-associated vascular changes and pathology. In the case of retina, it is likely that both locally produced VEGF in the retina and circulating VEGF (cVEGF) molecules contribute to retinopathy development.