Abstract
Age-related macular degeneration (AMD) is one of the leading causes of blindness worldwide. Vision loss from the neovascular form is associated with the invasion of choroidal endothelial cells into the neural retina to form vision-threatening macular neovascularization (MNV). Anti-angiogenic agents are the current standard of care but are effective in only ~50% of AMD cases. The molecular mechanisms involved in invasive MNV point to the importance of regulating signaling pathways that lead to pathologic biologic outcomes. In studies testing the effects of AMD-related stresses, activation of the Rho GTPase, Rac1, was found to be important for the choroidal endothelial cell invasion into the neural retina. However, current approaches to prevent Rac1 activation are inefficient and less effective. We summarize active Rac1-mediated mechanisms that regulate choroidal endothelial cell migration. Specifically, we discuss our work regarding the role of a multidomain protein, IQ motif containing GTPase activating protein 1 (IQGAP1), in sustaining pathologic Rac1 activation and a mechanism by which active Rap1, a Ras-like GTPase, may prevent active Rac1-mediated choroidal endothelial cell migration.
Highlights
Maccarone Rita and Annamaria TisiAge-related macular degeneration (AMD) is one of the leading causes of blindness worldwide [1]
Vision loss from neovascular AMD often occurs from the invasion of endothelial cells from the choroid into the neural retina [13,14], where they are joined by other cell types to proliferate into neovascular lesions, known as type-2 macular neovascularization (MNV) [15]
To identify effectors involved in choroidal endothelial cell migration, we developed a physiologically relevant human coculture assay using choroidal endothelial cells and retinal pigment epithelial (RPE) cells to recapitulate events surrounding choroidal endothelial cell transmigration of the RPE monolayer, a necessary step in type-2 MNV [24]
Summary
Age-related macular degeneration (AMD) is one of the leading causes of blindness worldwide [1]. Endothelial cell migration involves dynamic actin cytoskeletal rearrangements that promote the formation of a leading edge highlighted by cell protrusions (i.e., lamellipodia and filipodia) and the retraction of the trailing edge [23] This process is regulated by several effectors downstream of different signaling cascades (i.e., Rho family of GTPases, PI-kinases, Ca2+ /calcineurin, as examples). Studies have since demonstrated that Rac is activated in choroidal endothelial cells by several AMD-associated stresses, tumor necrosis factor alpha (TNFα) [26], an example of an inflammatory cytokine; vascular endothelial growth factor (VEGF) [27,28,29,30,31,32] or C-C motif chemokine 11 (CCL11) [30], angiogenic stimuli; reactive oxygen species (ROS) [26]; and 7-ketocholesterol (7KC) [29,33], an oxidized cholesterol that accumulates in human Bruch’s membrane (Figure 1).
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