Role of Endothelial Cell Stiffening in Choroidal Atrophy Associated With Dry Age-Related Macular Degeneration
- Author(s): Cabrera, Andrea Paulina
- Advisor(s): Ghosh, Kaustabh
- et al.
Age-related macular degeneration (AMD) is the leading cause of blindness in the aging population. Recent studies have implicated choriocapillaris (CC) dropout and choroidal thinning in AMD pathogenesis, potentially mediated by hypoxia-induced retinal pigment epithelium dysfunction. However, the precise mechanism underlying choroidal atrophy remains unknown. The goal of this research was to address this vital gap in our mechanistic understanding of choroidal atrophy associated with dry AMD.
Since complement activation, a major risk factor for dry AMD, leads to the deposition of membrane attack complex (MAC; C5b-9n) on choroidal vessels,it may lead to choroidal endothelial cell (EC) atrophy and the observed loss of CC in AMD eyes. Interestingly, MAC deposition also occurs in young non-AMD eyes, thus indicating that specific age-related factors may contribute to MAC-induced choroidal degeneration in AMD eyes. Since aging, a major nonmodifiable risk factor for AMD, has been shown to increase stiffness of retinal vessels and enhance pro-inflamatory cues in non-opthalmic vessels such as aorta and arteries, the central hypothesis of this research was that aging increases CC stiffening that, in turn, enhances EC susceptibility to MAC injury.
Findings from the current research revealed for the first time that aging leads to choroidal EC stiffening that in turn, contributes significantly to the increased susceptibility to MAC injury. Further, these studies showed that the stiffening of aged choroidal ECs is cytoskeletal-mediated. Remarkably, reducing age-induced EC stiffness prevented MAC injury. Taken together, these novel findings not only elucidate a key role of EC stiffness but also identify potentially new targets (e.g. Rho-mediated cytoskeletal stiffening) for more effective therapies in the future.