BOSTON -- Alterations in blood vessel dilation lie at the heart of coronary artery health: When vessels dilate, blood and oxygen supplies successfully reach the heart. When vessels contract, blood and oxygen are diminished, leading to coronary artery disease.
The biology behind this course of events, known as vasodilation, occurs through nitric oxide, a gaseous molecule synthesized by an enzyme called eNOS, which relaxes the vascular smooth muscle cells lining the outer layer of coronary vessels. If, during this course of events, nitric oxide (NO) encounters another group of molecules known as reactive oxygen species (ROS), then NO is inactivated, and instead of dilating, blood vessels contract. In other words, ROS are harmful.
But a paper by Ruhul Abid, MD, PhD, of BIDMC's Center for Vascular Biology Research upends this long-held notion, demonstrating that ROS has another, beneficial role in the activation of eNOS and the nitric oxide production process – and, in fact, is necessary to maintain coronary vasodilation.
This paradoxical discovery, published last spring in the American Heart Association journal Arteriosclerosis, Thrombosis, and Vascular Biology, was recently selected from more than 650 entries as the journal's most outstanding Vascular Biology paper of 2010. Abid will receive the AHA's 2011 Werner Risau New Investigator Award in Vascular Biology on April 29 in Chicago for this groundbreaking work.
"ROS are generally believed to play harmful roles in microvascular tone in hypertension, angiogenesis and vascular complications of arthritis and diabetes," explains Abid. "As a result, it's been widely assumed that by reducing ROS oxidants, you can improve cardiovascular function." In fact this is the premise underscoring the use of antioxidants, such as Vitamins E and C and beta carotene, to help prevent heart disease.
"But our findings now suggest that these high oxidant levels often found in the microvasculature walls in coronary artery disease [CAD] may not be just an undesirable by-product," he adds. "Instead, the increased ROS levels found in CAD may be a homeostatic response necessary to increase the synthesis of nitric oxide and thereby increase coronary dilation and blood supply to the heart."
In other words, ROS are also helpful.
Abid's laboratory arrived at this discovery after first studying human endothelial cells from coronary arteries.
"We reduced levels of ROS in these cell cultures, assuming that this would make the cells happy," he explains. "But we came up with totally opposite results. The coronary endothelial cells stopped growing and migrating."
Further investigations revealed that when ROS were reduced, the PI3K-Akt-eNOS pathways – which are essential for cell growth and migration and the production of nitric oxide – were also experiencing decreased activation. "We thought this might explain why the endothelial cells were so unhappy," says Abid.
To test this hypothesis, the investigators studied an NAPDH oxidase knockout mouse model containing a 50 percent reduction in ROS. (NAPDH oxidase is a major source of ROS in endothelial cells.) After isolating the intact coronary arterioles from the heart of the knockout mouse, as well as those from a wild-type control mouse, Abid's team exposed the coronary blood vessels from both groups of mice to vascular endothelial growth factor (VEGF), a protein known to promote blood vessel growth.
"Normal, healthy blood vessels will become dilated when they are exposed to VEGF," Abid explains. "Conversely, without ROS, the vessels of the knockout mice should have dilated even more when VEGF was introduced." But that wasn't what the scientists found.
"As we had hypothesized, by inhibiting ROS, we were also inhibiting the PI3K-Akt pathway – as well as the production of nitric oxide by eNOS. We essentially came to the conclusion that if ROS is reduced too much, blood vessels contract instead of dilate, and adequate blood supply is unable to reach the heart."
"Dr. Abid has made an important discovery regarding the role of oxidative stress on VEGF signaling in the vasculature," notes Frank Sellke, MD, PhD, the Karl Karlson and Gloria Karlson Professor and Chief of Cardiothoracic Surgery at Brown Medical School and Lifespan Hospitals. "This may have relevance in clinical medicine, especially as it applies to atherosclerotic heart disease and regenerative medicine."
According to Abid, follow-up studies will help guide investigators and clinicians as to whether or not to interfere with the high redox levels often present in coronary microvascular disease.
"As we have now learned, by lowering oxidant levels you could be paradoxically affecting redox-dependent signaling and vasodilation, and therefore, predisposing patients to an increased risk of myocardial ischemia. Going forward, we aim to understand the permissive role of ROS in maintaining coronary vasodilation," he adds. "We think this may have an impact on the development of therapeutic modalities for vascular diseases, and may help explain the apparent failure of antioxidants in large clinical trials, such as the HOPE trial."
The AHA's Werner Risau New Investigator Award in Vascular Biology was established in honor of Dr. Werner Risau, an investigator who formulated key concepts for the regulation of angiogenesis, challenged the prevailing dogmas about angiogenic factors, and proposed the now accepted hypothesis that several growth factors act sequentially to mediate vasculogenesis, angiogenesis, and vascular remodeling.
Abid's coauthors on this paper included BIDMC investigators Scott M. Damrauer, Christiane Ferran, and Monica Lee, and Brown University Alpert Medical School investigators Jun Feng and Frank Sellke.
The study was supported by grantsfrom the American Heart Association and the National Institutes of Health.
BIDMC is a patient care, teaching and research affiliate of Harvard Medical School, and consistently ranks in the top four in National Institutes of Health funding among independent hospitals nationwide. BIDMC is a clinical partner of the Joslin Diabetes Center and a research partner of the Dana-Farber/Harvard Cancer Center. BIDMC is the official hospital of the Boston Red Sox. For more information, visit www.bidmc.org.