Xiaodong Cheng, PhD
Xiaodong Cheng, PhD

Recent research on “Epac1 inhibition ameliorates pathological angiogenesis through coordinated activation of Notch and suppression of VEGF signaling” from the collaboration between the labs of Xiaodong Cheng, PhD, professor in the Department of Integrative Biology and Pharmacology, and Wenbo Zhang, PhD, professor in the Department of Ophthalmology and Visual Sciences at UTMB has been published in the January issue of Science Advances.

Fang Mei, MD, assistant professor; and Wenli Yang, PhD, research associate in the Department of Integrative Biology and Pharmacology; as well as Hua Liu, PhD, assistant professor of ophthalmology & visual sciences at UTMB, are the co-first authors of the paper.

Cheng’s research focuses on the stress response signal cyclic adenosine monophosphate (cAMP), which is significant in managing many physiological and pathophysiological processes, while Zhang’s research focuses on mechanism of ischemic retinopathy. In the collaborated work, they examined the roles of exchange proteins directly activated by cAMP (Epac), specifically Epac1, in the formation of new blood vessels from existing vasculature, a process called angiogenesis. While physiological angiogenesis is vital for normal growth and development, pathological angiogenesis plays important roles in abnormal vessel growth, which contributes to the pathogenesis of diverse human diseases such as cancer, retinopathies, and cardiovascular disorders.

The collaborators began their research by using a proven mouse model of retinopathy of prematurity (ROP) called oxygen induced retinopathy (OIR). ROP occurred after World War II, when advanced technology allowed physicians to save babies born prematurely by placing them in incubators. However, the increased oxygen proved harmful to the development of the growth of the babies’ eyes causing blindness.

Scientists soon connected that babies born prematurely are very similar to rodent babies, who are born blind for the first week of their life, in that their retinas are not fully developed at the time of birth. The OIR mouse model has since become a powerful tool for studying vascular pathology in the retina.

Cheng and Zhang’s teams discovered that Epac1 is not required for the normal retinal development. However, they found that the levels of cAMP and Epac1 were increased in the OIR model, that knockout mice without Epac1 showed less uncontrolled neovascularization, essentially protecting the mice from pathogenic angiogenesis. Researchers validated the role of Epac1 in pathogenic angiogenesis using two additional rodent models, carotid artery ligation and Matrigel plus assays.

“One of the exciting discoveries in the study is that blockade of Epac1 results in less retinal neovascularization and more vascular repair (less avascular area),” Liu said. “This feature is highly desirable in clinic as current anti-VEGF agents block both pathological and physiological angiogenesis, and repeated injections are needed since retinal ischemia persists.”

“Of course, the puzzle is, why are these molecules important for pathogenic angiogenesis,” Cheng continued. “Why are they not important for normal vascular formation? We needed to understand the mechanism in order to answer that question.”

An abundance of literature already exists on normal angiogenesis. The vascular endothelial growth factor (VEGF), which stimulates the growth of new blood vessels, works with Notch signaling in a yin-and-yang sort of way to produce the healthy growth of blood vessels. Notch signaling works as a communicator between two cells and serves as a counter-balance factor to VEGF to ensure order of the growth of new vessels.

“What we found, unsurprisingly, is the Epac pathway can synergize with the VEGF pathway to enhance it,” Cheng said. “What we didn’t anticipate to see is that not only does the Epac pathway synergize VEGF, but it also blocks the Notch pathway.”

This occurs because Epac is a stress signal, which is activated in pathogenic conditions. During regular growth, the cAMP protein is not activated which leaves the VEGF and Notch pathways to perform normally. However, under conditions of stress, the cAMP and Epac1 levels increase, causing a heightened activation in Epac which synergizes with the VEGF while blocking the Notch signaling to propel uncontrolled neovascularization and pathologic angiogenesis.

“It was important that we established a clear role that the Epac pathway plays in pathogenic angiogenesis and provided an interesting mechanism for that,” Cheng said. “This opens up potential for developing additional novel therapeutic treatments for the types of vascular proliferative diseases like diabetic retinopathy, which is the leading cause of blindness among the working-age population.”

According to the United States Centers for Disease Control and Prevention, more than 30 million Americans suffer from diabetes, with a third of that population aged 40 or over also suffering from diabetic retinopathy and related diabetic eye disease.

The Epac proteins are an excellent target for developing drugs, because of predicted low on-target toxicity. Since the protein is already known to not play an important role in normal function, it can be targeted therapeutically with much less risk of toxicity.

“Of course, the challenge is developing a very specific modulator to control that, an active area of research in our laboratory” Cheng said. “That’s what is exciting. This has opened up our understanding of the role the signal pathways play in these pathogenic conditions and identifies a novel and exciting drug target for these diseases.”