Proteins that regulate BP, flow identified
October 11, 2010
Scientists have identified key players in a
little-known biochemical pathway that appears to regulate blood pressure.
The findings have evolved from studies conducted by Jeffrey S. Isenberg,
Eileen M. Bauer, and their colleagues at the University of Pittsburgh School
of Medicine .
“Identifying and unraveling this important pathway for blood pressure
regulation could lead to a better understanding of who will get high blood
pressure and why, as well as allow us to develop better drugs to treat these
patients,” Isenberg said.
“Poorly controlled hypertension is a major risk factor for heart attacks and
heart failure, stroke and kidney failure,” he added.
Isenberg and collaborator David D. Roberts, of the National Cancer
Institute, National Institutes of Health , have been exploring uses of
nitric oxide signaling.
The cells that line blood vessels, called the endothelium, produce NO in a
few biochemical steps. NO promotes blood vessel dilation and increases blood
flow. Conversely, endothelial dysfunction, along with loss of NO production,
is known to be involved in the development of many forms of cardiovascular
disease, including hypertension.
Through cell culture and mouse experiments, the researchers found that a
protein called thrombospondin-1 (TSP1) and its receptor, CD47, inhibit
activation of the endothelial-based enzyme called endothelial nitric oxide
synthase (eNOS), which in turn limits the production of NO and thus prevents
blood vessels from relaxing and blood pressure from dropping. Circulating
TSP1, at levels consistent with those found in the blood stream, is capable
of inhibiting activation of endothelial-based eNOS and thus blocking NO
“For some time now, it has not been clear what role TSP1 served in the
blood. Experiments in cells told us TSP1 could alter NO signaling. But TSP1
is a protein too large to cross through the endothelial layer and into the
blood vessel wall, so it was not obvious how it could alter the muscle tone
of the arteries,” Isenberg said.
“We also knew that mice genetically engineered to not produce TSP1 or CD47
showed more NO-based blood flow and blood vessel dilation. This suggested to
us that perhaps circulating TSP1 was altering the ability of the endothelium
to make NO by acting on eNOS,” he added.
The findings have been published in the early online version of