Professor Louis Bouchard and alumna Julia Mack are part of UCLA team to find a protein which helps ward off inflammation.
In a study published in November, researchers led by Professors Luisa Iruela-Arispe of UCLA Molecular, Cell, and Developmental Biology and physical chemist Louis Bouchard of UCLA Chemistry & Biochemistry and UCLA Bioengineering, discovered several roles for the protein NOTCH1 in the response of blood vessels to physical forces caused by blood flow. The work demonstrates that NOTCH1 serves as a sensor for and activates cellular responses to blood flow.
Professor Luisa Iruela-Arispe, Dr. Julia Mack, Professor Louis Bouchard.
The lead author on the Nature paper, Dr. Julia Mack (Ph.D. ’04 Chemistry, Kaner group), is a chemistry and biochemistry alumna and she is currently a postdoctoral researcher in Iruela-Arispe’s group.
The research was featured in UCLA Newsroom’s UCLA Research Alert section on December 11, 2017.
Endothelial cells, the cells that line the interior of blood vessels, are sensitive to the shear forces generated by flowing blood. These cells adapt their shape and function in response to the type and amount of physical force they experience.
Because blood flows in the body are not uniform, certain areas of blood vessels are more vulnerable to vascular diseases like atherosclerosis, the deposition of plaque in an artery, that may lead to heart attack or stroke. Understanding how endothelial cells sense and respond to changes in blood flows can inform medical knowledge of how to treat vascular diseases.
NOTCH1 has known roles in embryonic blood vessel development. Since it remains present in adulthood, the researchers assessed the role of NOTCH1 in adult blood vessels. Using cell culture flow chambers to represent blood vessels, the researchers showed that endothelial cells increase the amount of NOTCH1 expression in response to increasing fluid shear forces. Cells experiencing high shear elongated themselves parallel to the direction of fluid flow and spaced themselves out regularly.
However, cells lacking NOTCH1 grew in a disoriented manner and grew too densely. These cells also did not form proper connections with neighboring cells. Proper connections with neighboring cells are necessary to stop the blood vessels from leaking.
When mice that lacked NOTCH1 were given a high cholesterol stimulus, they developed more plaque deposits than normal mice in blood vessels near the heart. These mice were also prone to aortic inflammation under normal conditions. In mice, the levels of NOTCH1 were higher in endothelial cells located in regions of high, uniform shear versus regions of low shear or disturbed flow. These results suggest NOTCH1 offers protection against certain vascular diseases and is important for preventing inflammation.
Many thanks to Joseph Ong for writing this article. Photo by Penny Jennings/UCLA Department of Chemistry and Biochemistry.