Abstract
Purpose :
Age-related macular degeneration (AMD) is the leading cause of blindness in the US, yet the mechanisms that underlie its initiation and progression remain elusive. In AMD, both pathological proliferation and involution of choroidal microvasculature are implicated. New imaging technologies suggest microvascular flow deficits as among the earliest detectable changes in the disease. Therefore, we sought to investigate the responsiveness of choroidal microvascular endothelial cells to hemodynamic shear stresses to test the hypothesis that shear-responsive expression across the choroidal microvasculature dictates spatial susceptibility to AMD pathology.
Methods :
Human choroidal endothelial cells were cultured in a perfusable microfluidic unit and subjected to physiologic and pathophysiologic (excess and insufficient) levels of shear stress by pressure-driven flow. RNA and protein were collected to analyze shear-sensitive gene expression relative to static controls. Confocal microscopy of human donor eyes was performed after fluorescent labeling of the choroidal vasculature via UEA lectin and immunostaining for shear-responsive proteins to investigate potential spatial correlations.
Results :
A cohort of shear responsive genes were identified and validated via transcriptomic profiling and immunoblotting. Furthermore, immunostaining of human donor eyes revealed correlations between abundance of shear stress-sensitive targets and predicted shear stress across the choroidal microvasculature in human donor eyes.
Conclusions :
The findings suggest that hemodynamic shear stress governs choroidal endothelial cell gene expression, may help to explain the asymmetric progression of this pathology, and identify hemodynamics as a potential therapeutically targetable stimulus.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.