New research delves into the molecular and cellular mechanisms behind angiogenesis and reveals the significance of Akt and R-Ras-Akt to endothelial lumenogenesis and ischemic tissue recovery, respectively. These findings were published in Nature Communications last week.
"Our research shows that the formation of fully functional blood vessels requires activation of protein kinase Akt by a protein called R-Ras, and this mechanism is necessary for the formation of the hallow structure, or lumen, of a blood vessel." says Masanobu Komatsu, Ph.D., associate professor at Sanford Burnham Prebys Medical Discovery Institute (SBP). "The findings are important because they shed new light on the biological process needed to increase blood flow in ischemic tissues."
Previous efforts to treat ischemia by creating new blood vessels have focused on delivering angiogenic growth factors like vascular endothelial growth factor (VEGF) to ischemic sites. But all of these studies, including more than 25 Phase II and III clinical trials, have failed to offer significant benefit to patients.
Komatsu's research team used a combination of 3D cell culture and living tissue to show that VEGF promotes vascularization, but the vessel structures formed are chaotic, unstable, and non-functional. "Functional vessels need to have a lumen; a pipe-like opening that allows oxygenated blood and nutrients to travel through the body," explains Komatsu, "and VEGF alone cannot fully support the formation of such a vessel structure."
"Generating new blood vessels is similar to the way trees grow; sprouts develop from existing vessels and then branch out further and further to restore vascularity, says Fangfei Li, Ph.D., postdoctoral associate in Komatsu's lab and lead author of the paper. "This study shows that there are distinct steps and signals that control the process.
"First, VEGF activates Akt to induce endothelial cells to sprout. Then, R-Ras activates Akt to induce lumen formation," explains Li. "The second step involving Akt activation by R-Ras stabilizes the microtubule cytoskeleton in endothelial cells, creating a steady architecture that promotes lumen formation," explains Li.
"We propose that VEGF and R-Ras activation of Akt signaling are complementary to each other, both are necessary to generate fully functional blood vessels to repair ischemic tissue," says Komatsu. "Our next step is to work toward promoting the combined signaling of Akt in clinical studies; prompting R-Ras activation through either gene therapy or pharmacologically in parallel with VEGF therapy," adds Komatsu.