AMP-activated protein kinase is a key regulator of retinal vascular permeability

Pathological hyperpermeability accompanies many blinding retinopathies. Despite important therapeutic breakthroughs benefitting many but not all retinopathy patients, the intracellular signalling underlying retinal leakage is still poorly understood. We have developed an ex-vivo model, which allowed us to measure and manipulate acute vascular permeability in the intact rodent retina, and combined measurements with immunohistochemical analyses of signal transduction. This ex-vivo retina platform proved to be an easily accessible and reliable tool for systematic identification of regulators of vascular permeability through small molecule antagonists/agonists and siRNA. By using this model, we showed that AMPK was a key mediator of VEGF- and bradykinin-induced permeability by acting downstream of Ca2+ and CAMKK, and upstream of eNOS/VE-cadherin as well as p38/HSP27. Accordingly, AMPK agonist potently induced retinal vascular leakage, a finding of major importance for their use as therapeutic agents in the treatment of e.g. cancer or metabolic syndrome.