One of the strategies under development to tackle age-related ischemia, in which blood flow to a limb becomes insufficient due to vascular damage or dysfunction, is to attempt to use signaling mechanisms to spur the development of new blood vessels that bypass the damaged area. Results to date have been mixed, and as the researchers here note, this is probably because the process of blood vessel growth is complex and staged. Simple treatments employing a single signal molecule are unlikely to make much headway.
A new study identifies a signaling pathway that is essential for angiogenesis, the growth of new blood vessels from pre-existing vessels. The findings may improve current strategies to improve blood flow in ischemic tissues. "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. 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. The 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, 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. 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. The second step involving Akt activation by R-Ras stabilizes the microtubule cytoskeleton in endothelial cells, creating a steady architecture that promotes lumen formation. 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. 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."