Bioactive metabolites derived from the cytochrome P450 (CYP) pathway have been shown to resolve the abnormal vascular growth associated with age-related macular degeneration (AMD). These metabolites, which act as second messengers, can regulate the expression of leukocyte adhesion molecules, changing how immune cells are recruited to areas of disease and injury and getting around the link between inflammation and choroidal neovascularization (CNV). When CNV is curbed, the leaking and rupture of these abnormal blood vessels in the retina is reduced, protecting against retinal detachment.
To study the role of CYP pathway–derived lipid metabolites in regulating neovascular disease, scientists based at the Massachusetts Eye and Ear Infirmary used transgenic mice with altered CYP lipid biosynthetic pathways in a mouse model of laser-induced CNV. This preclinical model allowed the scientists to discover that the CYP-derived lipid metabolites epoxydocosapentaenoic acids (EDPs) and epoxyeicosatetraenoic acids (EEQs) are vital in dampening CNV severity.
Details of the work appeared August 21 in the Proceedings of the National Academy of Sciences, in an article entitled “Cytochrome P450 Monooxygenase Lipid Metabolites Are Significant Second Messengers in the Resolution of Choroidal Neovascularization.” The article suggests that EDPs and EEQs could have significant therapeutic implications, not only for AMD, but also for other inflammatory disorders. That is, by regulating inflammatory immune cells and moderating angiogenic processes, EDPs and EEQs could be helpful against conditions besides AMD that involve inflammation and angiogenesis, such as cardiovascular disease and cancer.
In advanced AMD, blood vessels in the retina begin to sprout new, abnormal blood vessels that grow over the retina’s surface. These new vessels are immature and can leak, rupture, or cause retinal detachment. Such cases, termed neovascular or “wet” AMD, account for 10% to 15% of AMD cases, develop abruptly, and rapidly lead to substantial vision loss.
Previous research has largely ignored the role of immune cells in advanced AMD, but the PNAS report suggests that they are likely are a major contributor in the pathologic process. The researchers identified key compounds of the CYP pathway, a major family of enzymes, and showed that the compound can influence angiogenesis, changing how immune cells are recruited to areas of disease and injury.
“Specifically, overexpression of the monooxygenase CYP2C8 or genetic ablation or inhibition of the soluble epoxide hydrolase (sEH) enzyme led to increased levels of EDP and EEQ with attenuated CNV development,” the authors of the PNAS article wrote. “In contrast, when we promoted the degradation of these CYP-derived metabolites by transgenic overexpression of sEH, the protective effect against CNV was lost.”
The most common cause of elderly blindness in the developed world, AMD is a chronic, progressive disease affecting as many as 11 million Americans, and that number is expected to double by 2020. Globally, approximately 196 million are projected to develop AMD by 2020. The risk of developing AMD increases from 2% for those ages 50–59, to nearly 30% for those over the age of 75.
“Given the high prevalence and progressive nature of neovascular eye disease, the ability to stabilize bioactive lipids that mitigate or halt disease is of great and increasingly therapeutic significance,” said corresponding author Kip Connor, Ph.D., a vision scientist at Massachusetts Eye and Ear Infirmary. “It is our hope that emerging technologies and future studies will expand on our work and ultimately lead to safe, targeted, and cost-effective therapies that markedly improve visual outcomes and quality of life for patients suffering from these debilitating eye diseases.”
“Our research shows how rapidly fundamental knowledge of physiology and regulatory biology can be translated to practical solutions for a major type of blindness,” said co-author Bruce Hammock, Ph.D., a scientist affiliated with the UC Davis department of entomology and nematology and the UC Davis Comprehensive Cancer Center. Dr. Hammock expressed hope that the team Dr. Connor has organized will “find a solution to a devastating human health program.”
“Although we do not fully understand how and why AMD develops,” noted Dr. Connor, “additional mechanisms that regulate abnormal blood vessel growth in the eye beyond what we currently know could open up a range of possibilities for new research and treatments for AMD.”