PDGF Receptor Alpha Signaling Is Key for Muller Cell Homeostasis Functions

Muller cells, the major retinal macroglia, are key to maintaining vascular integrity as well as retinal fluid and ion homeostasis. Although platelet derived growth factor (PDGF) receptor expression in Muller glia has been reported earlier, their actual role for Muller cell function and intimate interaction with cells of the retinal neurovascular unit remains unclear. To close this gap of knowledge, Muller cell-specific PDGF receptor alpha (PDGFR alpha) knockout (KO) mice were generated, characterized, and subjected to a model of choroidal neovascularization (CNV). PDGFR alpha-deficient Muller cells could not counterbalance hypoosmotic stress as efficiently as their wildtype counterparts. In wildtypes, the PDGFR alpha ligand PDGF-BB prevented Muller cell swelling induced by the administration of barium ions. This effect could be blocked by the PDGFR family inhibitor AC710. PDGF-BB could not restore the capability of an efficient volume regulation in PDGFR alpha KO Muller cells. Additionally, PDGFR alpha KO mice displayed reduced rod and cone-driven light responses. Altogether, these findings suggest that Muller glial PDGFR alpha is central for retinal functions under physiological conditions. In contrast, Muller cell-specific PDGFR alpha KO resulted in less vascular leakage and smaller lesion areas in the CNV model. Of note, the effect size was comparable to pharmacological blockade of PDGF signaling alone or in combination with anti-vascular endothelial growth factor (VEGF) therapy-a treatment regimen currently being tested in clinical trials. These data imply that targeting PDGF to treat retinal neovascular diseases may have short-term beneficial effects, but may elicit unwarranted side effects given the putative negative effects on Muller cell homeostatic functions potentially interfering with a long-term positive outcome.