In people with a healthy vascular system, arteries adjust their size to allow sufficient blood flow to reach different organs. This process is called artery remodeling.
For more than a decade, Yale researchers have investigated the processes related to artery remodeling. A foundational paper published in 2014 in eLIFE by Baeyens et al. showed that endothelial cells that line arteries have a ‘fluid shear stress set point.’ Endothelial cells in arteries guide vessel remodeling so that the fluid shear stress from blood flow is close to the set point.
“The endothelial cells lining our arteries function like a smart thermostat, which knows when to turn on the heating or cooling system if the house becomes too cold or hot,” said Martin Schwartz, PhD, Robert W. Berliner Professor of Medicine (Cardiovascular Medicine) and professor of biomedical engineering and of cell biology. “If the shear stress dips too low, endothelial cells activate inflammatory and remodeling pathways to reduce the vessel size. If the shear stress is too high, blood vessels enlarge.”
People with conditions such as peripheral artery disease and coronary artery disease have arteries that have difficulty remodeling. This results in poor blood flow and ischemia, which causes pain and ultimately tissue damage, and, in some cases, death.
Yale researchers recently published a paper in Nature Cardiovascular Research investigating pathways that regulate vessels that remodel to become larger (or outward remodeling).
“Our hypothesis was that shear stress at the set point stabilizes the vessel. Only when shear stress stays below or above the set point for a long enough time does it lead to inward or outward remodeling, respectively,” said Hanqiang Deng, PhD, associate research scientist (cardiovascular medicine), first author of the paper.
“We thought that made good sense,” added Schwartz, senior author of the paper. “You wouldn’t want a brief change to cause vascular remodeling. You would only want remodeling to happen with a sustained change in blood flow.”
To carry out the research, they put endothelial cells under high shear stress and looked at the pathways that were activated. They identified a pathway, KLF2-BMPER-Smad1/5, that plays a role in high-shear stress outward remodeling.
The paper identified a specific antibody that targets this pathway and suggests that it is a potential therapeutic approach for ischemic disease.
“Our paper showed that BMP9/10 blocking antibodies, which inhibit the Smad1/5 pathway can effectively improve blood flow recovery from hind limb ischemia,” said Deng.
Deng recently received a career development award from the American Heart Association supporting his ongoing research to investigate endothelial fluid shear stress-mediated vascular remodeling. He plans to expand on this research by investigating additional pathways for artery remodeling in different vascular diseases, including hypertension, atherosclerosis, and diabetes.
“Through hard, meticulous work, Hanqiang, Martin, and their colleagues have uncovered a potential new pathway governing arterial remodeling,” said Eric Velazquez, MD, Robert W. Berliner Professor of Medicine and chief of Yale Cardiovascular Medicine. “The construct of tightly controlling blood vessel growth in response to injury and disease would be transformative to science and clinical care. I am excited to see how the story they are writing continues.”
This research builds on previous Yale work, including a paper in the EMBO Journal earlier this year, identifying a protein, Latrophilin-2, activated by changes in blood flow.
“It’s important to remember that this work came out of a basic science desire to understand the processes associated with vascular remodeling,” said Schwartz. “Once you understand that, you can start developing treatments. But the basic science comes first.”
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