“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,” Dr. Komatsu said.
“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.
Dr. Komatsu and his colleagues, Dr. Fangfei Li and Dr. Junko Sawada, 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,” Dr. Komatsu explained.
“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,” Dr. Li added.
“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,” Dr. Li said.
“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,” Dr. Komatsu said.
“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.”
Fangfei Li et al. 2017. R-Ras-Akt axis induces endothelial lumenogenesis and regulates the patency of regenerating vasculature. Nature Communications 8, article number: 1720; doi: 10.1038/s41467-017-01865-x