UC Riverside

The goal of this research was to understand the role of cell- and subendothelial matrix-dependent mechanical cues in retinal endothelial cell (EC) activation associated with diabetes and to identify novel molecular targets for effective suppression of diabetic retinal EC activation. Endothelial activation is a hallmark of high glucose (HG)-induced retinal inflammation associated with diabetic retinopathy. Here I identified that HG-induced upregulation of lysyl oxidase (LOX), a collagen-crosslinking enzyme, in retinal capillary endothelial cells (ECs) leads to subendothelial matrix stiffening that, in turn, promotes retinal EC activation. Further, I showed that (i) HG-induced subendothelial matrix stiffening significantly impairs Transient Receptor Potential Vanilloid 4 (TRPV4, a mechanosensitive Ca2+ channel) expression and activity, (ii) TRPV4 impairment alone is sufficient to promote high glucose-induced retinal EC activation, (iii) LOX inhibition prevents high glucose-induced impairment of TRPV4 and, consequently, anti-inflammatory nitric oxide. Finally, I showed that the inhibitory effect of matrix stiffening on TRPV4 is mediated, at least in part, via the canonical Rho/ROCK mechanotransduction pathway that directly controls EC stiffness. Together, these findings identify a crucial role of Rho/ROCK-mediated TRPV4 signaling in diabetic retinal EC activation and implicate Rho/ROCK and TRPV4 as the novel anti-inflammatory target for management of early DR.