Topic Overview:
Cardiovascular disease is the No. 1 source of illness and death in adults in the United States. In 2006, the American Heart Association estimated that more than 81 million Americans had one or more forms of cardiovascular disease. That same year, cardiovascular disease accounted for 34.3 percent of all deaths.

Dr. Isenberg’s research involves nitric oxide (NO), a biogas produced by vascular endothelial cells that is a central regulator of cardiovascular health. NO signaling directs long-term regulation of angiogenesis.  In addition, it controls blood flow and hemostasis, modulates blood pressure and heart function, and suppresses inflammation. Conversely, the pathogenesis of stroke, myocardial infarction, hypertension, peripheral vascular disease, and other cardiovascular disorders often involves the loss of NO signaling.

Physiological levels of NO are also known to supercharge the protein thrombospondin-1 (TSP1), which guides vascular cell behavior through several cell-surface receptors, by more than 1,000-fold. In vitro, nanomolar concentrations of TSP1 are required to alter endothelial and vascular smooth muscle cell adhesion, proliferation, motility, and survival. Yet much lower levels of TSP1 are clearly functional in vivo.

TSP1 binding to its cognate receptor protein CD47 inhibits the NO signaling pathway by preventing cyclic guanosine monophosphate (cGMP) synthesis and subsequent activation of cGMP-dependent protein kinase. New data suggest that the TSP1-CD47 signaling nexus also limits NO production by suppressing endothelial nitric oxide synthase activity. This disruption of NO signaling allows TSP1 to constrict blood vessels; accelerate platelet aggregation; and, if sustained, inhibit angiogenic responses. Though important for hemostasis, acute antagonism of NO signaling by TSP1 becomes detrimental for tissue survival after ischemic injury.

Dr. Isenberg’s findings suggest that therapeutic approaches targeting TSP1 or CD47 can selectively increase NO signaling, resulting in improved healing after ischemia and ischemia-reperfusion injury, modulation of blood pressure, enhanced bioenergetics, and recovery from a deficit in NO-responsiveness related to aging.

Reporting in the October 2009 issue of Science Translational Medicine, Dr. Isenberg and colleagues from the National Cancer Institute identified just such a potentially exciting therapeutic target for the TSP1-CD47 pathway related to cancer treatment.

In mouse experiments, the team found that blocking the TSP1 molecule from binding to CD47 could give normal tissues nearly complete protection from standard and very high doses of radiation. “We almost couldn’t believe what we were seeing,” Dr. Isenberg said, adding that the protective effect took place in skin, muscle, and bone marrow cells. At the same time, CD47 suppression delayed the recurrence of tumors in radiation-treated mice.