Johns Hopkins researchers found that increased vascular endothelial growth factor ( VEGF) levels in the retina attract white blood into the retina , where they adhere to the walls of blood vessels, disrupting blood flow. Reducing VEGF or blocking it with an antibody caused the white blood cells to dissipate, opening the closed vessels and restoring blood flow to the area. The study published in the Journal of Clinical Investigation Insight
The inspiration for the study came from clinical observations for ranibizumab , a drug designed to block VEGF in patients with diabetic retinopathy and retinal vein occlusion. They saw that after VEGF was suppressed, the patients' conditions were not improved, but the treatment was improved .
To investigate, Campochiaro chose six genetically modified mice to overexpress VEGF when given a drug called doxycycline. After three days of VEGF overexpression, Campochiaro's team observed the telltale clumps of white blood cells collecting in the blood vessels of the retina. The researchers then stopped overexpressing VEGF in these mice, and 17 days later, they found that the white blood cell clumps had broken up and blood flow returned to areas of the retina that had been cut off.
The researchers then explored the cellular signals responsible for the vessel-plugging effects of VEGF. They found that when the blood cells interacted with VEGF, they were triggered to migrate into the blood vessels of the retina. The high levels of VEGF also activated a transcription factor, called NF-kappaB, which is responsible for the expression of many different kinds of proteins in the body.
Most importantly, it controls a cell adhesion molecule called VCAM-1 , which acts as an adhesive between many types of immune cells and blood vessels. The group then repeated their previous experiment, but administered an antibody to inhibit VCAM-1 while also increasing VEGF expression.
When compared to the inhibitor, the VCAM-1 inhibitor-treated mice showed significantly less blood cell clumps and better blood flow in the retinal blood vessels. This means that VEGF drives the early stages of diabetic retinopathy and retinal vein occlusion, as well as the late stages when vision is decreased, said Campochiaro.
However, hopefully that technology already in development will allow for continued delivery of anti-VEGF drugs and gene therapy to express anti-VEGF proteins in the eye and will make long-term treatment more feasible. Blocking VCAM-1 could add an additional benefit by further slowing vessel closure and progression of disease.
Diabetic retinopathy is the leading cause of blindness in the US Careful management of diabetes and frequent injections of an anti-VEGF agent are effective in reducing the progression to blindness in many patients, but each treatment carries the risk of adverse reactions or infection. Retinal vein occlusion is the second most common retinal vascular disease after diabetic retinopathy.