The UMSOM Discovered a New Vascular Health Signaling Molecule

Researchers have been racing to learn more about how this mysterious signaling molecule works to repair blood vessels damaged by a heart attack, stroke, or other cardiovascular event in the 25 years since the Nobel Prize was awarded for discovering the role that nitric oxide (NO) plays in the cardiovascular system. Researchers from the University of Maryland School of Medicine (UMSOM) and Wake Forest University (WFU) announced today a critical missing piece of the puzzle.

Their latest study, published in Nature Chemical Biology, discovered that heme, an iron-containing signaling molecule found in our blood and cells, binds to NO and transports it around the vascular system. This allows NO to control blood flow, blood pressure, clot formation, and maybe other signaling mechanisms involved in the healing of injured blood arteries.

While NO’s signaling responsibilities have been intensively researched over the last three decades, researchers still don’t know how this short-lived molecule goes from blood to signaling targets in the blood vessel wall. To fill this void, a team lead by UMSOM and WFU researchers studied the creation of a stable NO intermediate known as NO-ferroheme. In animal experiments, the researchers found that NO-ferroheme is carried in blood, typically coupled to albumin, and travels to blood vessels, causing them to widen, decreasing blood pressure.

“We know that nitric oxide — with its extremely short half-life of less than a second in blood — must have a way of moving through the bloodstream and into blood vessels via a stable mechanism,” said study lead author Anthony DeMartino, PhD, Assistant Professor of Medicine at UMSOM.  “We worked out the chemistry and the kinetics of how NO-ferroheme is physiologically generated in the test tube, and then demonstrated how it works in an animal model, which provides strong evidence of our hypothesis.”

The research team decided to look at heme, which is best recognized for its involvement in oxygen supply (through hemoglobin) in the blood but is also a typical NO signaling target. In a laboratory setting, they mixed ferric heme (an oxidized form of the chemical that can cause cellular harm) with NO and the antioxidant glutathione (present in high levels in most cells) to see how they would respond.

They discovered that in the presence of glutathione, NO responds quickly by attaching to the heme, generating a stable, reduced heme signaling molecule known as NO-ferroheme. The researchers then opted to investigate the compound’s effects on two of NO’s signature properties: vasodilation and regulation of blood platelet aggregation (which promotes blood clot formation). When NO-ferroheme was given to mice, it showed vasodilatory effects, increasing blood flow in the arteries and reducing blood pressure. NO-ferroheme also reduced platelet aggregation in human blood platelet samples.

“My laboratory has worked for more than two decades trying to understand how NO can diffuse in blood and in cells without being destroyed by reactions with other radicals and heme bound proteins like hemoglobin and myoglobin.  The stabilization of NO by forming NO-ferroheme allows it to diffuse across distances, almost like a chemical flying saucer, to directly bind to and activate target enzymes that control blood flow,” said study lead and corresponding author Mark T. Gladwin, MD, UMSOM Dean and Vice President for Medical Affairs, University of Maryland, Baltimore, and the John Z. and Akiko K. Bowers Distinguished Professor.  “The NO-ferroheme can also bind to albumin, which is the most abundant protein in our blood.  We hypothesize that NO-ferroheme-albumin can be developed as a drug to target different disease states where NO is impaired such as pulmonary hypertension, diabetes, and obesity.”

Dr. Gladwin and his lifelong collaborator and co-senior author Dany Kim-Shapiro, PhD, Professor and Chair of the Department of Physics at WFU, have been studying how NO is carried in red blood cells and regulates blood flow for more than two decades.

“One of the most surprising things that came out of our study was the role of the glutathione; both in the novel chemistry in forming the NO ferroheme and in its effects in vivo,” said Dr. Kim-Shapiro.  “We still have a lot more work to do to fully understand this.”

NO has numerous complex aspects that experts have yet to grasp. They understand it has Jekyll and Hyde properties, with good effects in the vasculature to enhance blood flow to arteries and tissues, as well as in immune defense, where macrophages employ NO to kill invading microorganisms. At the same time, NO is toxic in high doses and can be used by cancer cells to boost blood flow, allowing tumors to develop quickly or assisting cancer cells in spreading.

The discovery of NO-ferroheme as a biological “middleman” offers a crucial step toward understanding the intricate signaling processes of NO in both healthy and pathological situations.

The researchers plan to investigate how NO-ferroheme is transported into vascular cells to activate the observed signaling.

They also wish to look at the use of NO-ferroheme as a possible therapy. A critical need is for novel treatments to address blood vessel damage known as ischemia-reperfusion injuries. These injuries, which are caused by a lack of oxygen in the arteries as a result of a stroke or cardiac arrest, frequently result in irreversible tissue damage. The availability of a safe medicine that can swiftly restore blood flow to affected tissues could potentially help lessen the devastating impact of these cardiovascular catastrophes.

This study was co-authored by Qinzi Xu, MD, Assistant Professor of Medicine at UMSOM, and Jason Rose, MD, MBA, Associate Professor of Medicine and Associate Dean, Innovation & Physician Science Development at UMSOM. Wake Forest University in Winston-Salem, NC, and the University of Pittsburgh in Pittsburgh, PA, were also research co-authors.

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