Leveraging Nuclear Receptors as Targets for Pathological Ocular Vascular Diseases

Abstract

Vasculogenesis and angiogenesis are physiological mechanisms occurring throughout the body. Any disruption to the precise balance of blood vessel growth necessary to support healthy tissue, and the inhibition of abnormal vessel sprouting has the potential to negatively impact stages of development and/or healing. Therefore, the identification of key regulators of these vascular processes is critical to identifying therapeutic means by which to target vascular-associated compromises and complications. Nuclear receptors are a family of transcription factors that have been shown to be involved in modulating different aspects of vascular biology in many tissues systems. Most recently, the role of nuclear receptors in ocular biology and vasculopathies has garnered interest. Herein, we review studies that have used in vitro assays and in vivo models to investigate nuclear receptor-driven pathways in two ocular vascular diseases associated with blindness, wet or exudative age-related macular degeneration, and proliferative diabetic retinopathy. The potential therapeutic targeting of nuclear receptors for ocular diseases is also discussed.

Aryl Hydrocarbon Receptor (AHR) Ligands as Selective AHR Modulators (SAhRMs)

“…In AhR null mice, there is an increase in bone volume fraction and decreased bone turnover and effects of ligands are variable and age-dependent. Loss of the AhR induces choroidal neovascular (CNV) lesion formation, and in a mouse model of this lesion two AhR-active pharmaceuticals (leflunomide and flutamide) attenuated CNV pathogenesis [ 88 , 89 ]. In addition to the effects of various AhR ligands on the multiple disease models noted above, the AhR and its ligands influence multiple diseases by modulating the immune system, and this has been extensively reviewed [ 18 , 22 , 48 , 49 , 50 , 51 , 52 , 53 , 70 , 72 , 73 ].…”

Nuclear Receptor Atlases of Choroidal Tissues Reveal Candidate Receptors Associated with Age-Related Macular Degeneration

“…Nuclear receptors (NRs) are the largest superfamily of ligand-dependent transcription factors in the human genome. Functionally, they regulate a variety of cell homeostatic events and as such are important in many aspects of human development and disease [ 18 , 26 ]. Currently, there are a number of FDA-approved drugs on the market that target these receptors, accounting for approximately 16% of small molecule drugs [ 27 ], including several directed to systemic and neurodegenerative diseases that share common pathogenic pathways with AMD [ 28 , 29 , 30 ].…”

Ocular Therapeutics and Molecular Delivery Strategies for Neovascular Age-Related Macular Degeneration (nAMD)

“…Another angiostatic steroid and glucocorticoid analog [ 152 ], anecortave acetate (Retaane, Fast track designation FDA), has been investigated to treat neovascular AMD. It is known to block choroidal angiogenesis by inhibiting proteases responsible for cellular migrations [ 153 ].…”

“…It is known to block choroidal angiogenesis by inhibiting proteases responsible for cellular migrations [ 153 ]. An interesting observation concludes that it does not hinder retinal angiogenesis during its inhibitory activity [ 152 ]. Compared to triamcinolone, adverse side effects such as cataract development and increased ocular pressure are not observed.…”