The interaction of nitric oxide with heme proteins causes a cascade of intracellular events that leads to specific physiological changes within cells. For example, nitric oxide causes the smooth muscle cells surrounding blood vessels to relax, decreasing blood pressure. Nitric oxide plays an important role in the central and peripheral nervous systems; the overproduction of nitric oxide in brain tissues has been implicated in stroke and other neurological problems.

In the current study, investigators at the University of Pittsburgh School of Medicine (PA, USA; www.pitt.edu) tested the hypothesis that TSP1 inhibited NO formation by acting on the enzyme endothelial nitric oxide synthase (eNOS), which catalyzes the production of NO in the cells that line blood vessels.

They reported in the July 7, 2010, online edition of the journal Cardiovascular Research that TSP1, working through its receptor CD47, inhibited activation of eNOS, which in turn limited the production of NO, thus preventing blood vessels from relaxing and blood pressure from dropping. TSP1 was found to circulate in the blood stream at levels capable of inhibiting activation of eNOS and thus blocking NO production.

"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,” said senior author Dr. Jeffrey S. Isenberg, professor of medicine at the University of Pittsburgh School of Medicine. "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.”

"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,” said Dr. Isenberg. "Poorly controlled hypertension is a major risk factor for heart attacks and heart failure, stroke and kidney failure.”

The investigators are examining the possibility of developing a novel line of blood pressure-regulating drugs that would preserve eNOS activity by blocking the inhibitory action of TSP1 and CD47.

Related Links:
University of Pittsburgh School of Medicine