Why do nerve cells and blood vessels stop working together in diabetes?

Cellular mechanisms responsible for disruption of retinal neurovascular coupling in diabetes mellitus.

Retinal neurovascular coupling, which increases blood flow by dilating retinal microvessels in response to neuronal activity, is impaired in diabetic patients. This impairment can precede overt retinopathy but is correlated with the level of retinopathy when present. The proposed study addresses the mechanisms responsible for this functional abnormality for the first time.

Changes in retinal vessel diameter are being imaged in intact retina using infrared to avoid photoreceptor activation. The cellular basis of neurovascular coupling is being mapped functionally using stimuli to selectively activate photoreceptors (light), neurones (focal electrical stimulation or neurotransmitter application), glial cells (focal electrical stimulation, neurotransmitters, photolytic release of intraglial Ca2+), or blood vessels (eg arachidonic acid (AA) metabolites). Glial Ca2+-signals and the direct effect of putative gliovascular signals on isolated pressurised retinal arterioles are being recorded. Responses are being compared for diabetic (streptozotocin rat model) and age-matched control tissues in order to determine the site of signaling faults (eg neuroglial or gliovascular transmission).

The team has shown that the BK ion channel activity is decreased in the myocytes of diabetic retinal arterioles due to reduced expression of the beta1-subunit. This may reduce vascular responses to AA metabolites, which often target this channel. The team is also investigating expression and distribution of other candidate signalling molecules at transcript and protein level to identify the molecular basis of signal failure. The work will provide not just an understanding of how diabetes interferes with retinal blood flow regulation but also improved experimental tools for the investigation of neurovascular coupling in the eye.

In this study the team discovered a new process that could contribute to getting diabetic retinopathy. They studied support cells – called Muller glial cells – that are a vital part of the way that nerve cells in the retina send signals to the blood vessels. Results showed that Muller glial cells in the diabetic retina were not able to break down toxic proteins known as ‘advanced lipoxidation endproducts’. This is important because more of the chemicals that lead to these toxic proteins are produced by the body in diabetics. If the toxins aren’t broken down and cleared away, they can potentially build-up inside cells and cause damage. The team was excited to find that a drug that binds together with the toxic proteins was able to reduce the effect of diabetes in the eye. There’s still lots to understand, but this could lead to a new treatment to slow or delay diabetic retinopathy.

• McDowell RE, McGeown JG, Stitt AW, Curtis TM (2013) Therapeutic potential of targeting lipid aldehydes and lipoxidation end-products in the treatment of ocular disease. Future Med. Chem. (2013) 5(2), 189–211