A leading expert on the role of monocytes and macrophages (types of immune cells) in atherosclerosis and other chronic inflammatory conditions delivered the keynote address Nov. 7 at the USF Health Heart Institute’s 2^nd Annual Scientific Colloquium.

Gwendalyn Randolph, PhD, an immunologist by training, began her career by studying how innate immune cells travel around the body and along the way began discovering connections between cardiovascular disease, lipid metabolism and the gut.

USF Health Heart Institute Director Samuel Wickline, MD, with speakers at the Institute’s 2nd Annual Scientific Symposium. From left: David Lominadze, PhD, USF Health professor of surgery; Gwendalyn Randolph, PhD, Unanue Distinguished Professor of Pathology and Immunology at Washington University School of Medicine in St. Louis; Dr. Wickline; and Travis Jackson, PhD, USF Health associate professor of molecular pharmacology and physiology.

For the Heart Institute talk, Dr. Randolph, the Emil R. Unanue Distinguished Professor of Pathology and Immunology at Washington University School of Medicine in St. Louis, focused on research investigating what drives inflammation in atherosclerosis – the most common cause of heart attacks.  She shared her work on the trafficking of immune cells and the lipoproteins that carry cholesterol through the bloodstream to deposit inside the artery walls.

“Dr. Randolph’s work in the field of atherosclerosis has produced novel and important insights into the critical cell types that are responsible for forming atherosclerotic plaques in patients with heart disease,” said Samuel Wickline, MD, professor of cardiology and director of the USF Health Heart Institute. “She also has elucidated the molecular factors that attract these cells to plaques and cause them to grow and become unstable, which leads the plaques to break down and clot. This process can ultimately result in blockage of vessels that supply blood to the heart and brain, causing heart attacks and strokes.”

Research by Dr. Randolph, this year’s keynote speaker at the colloquium, has yielded new insights into how immune cells drive inflammation contributing to atherosclerotic plaques in heart disease.

Mouse model studies by Dr. Randolph and others have shown white blood cells, known as monocytes, contribute to the initial build-up of atherosclerotic plaques.

The cascade of events leading to atherosclerosis can take decades.  Initial damage to the inner wall (endothelium) of arteries under the influence of high cholesterol levels triggers a molecular signal that attracts monocytes to travel from the bloodstream into developing plaques. These recruited monocytes are converted into macrophages that take up (eat) the cholesterol trapped in blood vessels and eventually die off. But before that happens, they stay busy secreting molecules that drive plaque inflammation  and weaken the vessel wall, leading to plaque rupture, clotting, and coronary artery obstruction.

In terms of developing new therapies to halt or reverse atherosclerosis, Dr. Randolph said, her research suggests that upstream targeting of recruited monocytes — either before or just after these immune cells arrive in plaques — may be more beneficial than targeting the fat-laden macrophages known as foam cells. Experiments with fluorescent tracers indicate that monitoring endothelial cells lining the arterial wall may be a way to track monocyte migration, she added.

Thomas McDonald, MD, a professor in the USF Health Morsani College of Medicine’s Department of  Molecular Pharmacology and Physiology and member of the Heart Institute, listens to Dr. Randolph’s talk.

In addition to Dr. Randolph, two new faculty members recruited this summer to the USF Health Heart Institute – Travis Jackson, PhD, and David Lominadze, PhD — provided overviews of their National Institutes of Health-funded research.

Dr. Jackson, an associate professor in the Department of Molecular Pharmacology and Physiology, discussed his translational work in therapeutic hypothermia — investigating ways to optimize cold-shock proteins and cold-stress hormones to increase the benefits of cerebroprotective cooling for traumatic brain injury. Dr. Lominadze, a professor in the Department of Surgery, presented research looking into the interactions of blood cells and the endothelium, with the aim of better understanding the microcirculatory disorders associated with cardiovascular and cerebrovascular diseases.

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The USF Health Heart Institute is scheduled to move to the new USF Health Morsani College of Medicine building in Water Street Tampa in late February 2020.  Its annual scientific colloquium will be held in the new home next year, and continue to evolve with the growth of the Institute, Dr. Wickline said.

“We will expand the program to cover other topics of interest to the cardiovascular community such as genetic heart diseases, heart failure, peripheral vascular disease, and gene therapy.”

-Photos by Allison Long, USF Health Communications and Marketing

Preclinical cancer study has implications for inhibiting atherosclerotic plaque growth

Uncontrolled angiogenesis (new blood vessel growth) plays a critical role in the growth and spread of cancer. | Image courtesy of The Angiogenesis Foundation

The formation of new blood vessels, known as angiogenesis, is essential for embryonic tissue development, wound healing and regenerative functions.  But when this normal process goes awry, the oxygen and nutrients carried though blood vessels can spur tumor cells to multiply uncontrollably and lead to cancer in distant tissues.

Cancer medications inhibiting excessive growth of new blood vessels frequently target vascular endothelial growth factor (VEGF), the main driver of blood vessel formation in tumors.  While VEGF inhibitors have been a breakthrough in treating many cancers, the medications also cause cardiotoxic side effects, such as hypertension and blood clots, in some patients.

Seeking to improve selective targeting of tumor-associated vessels and the safety profile of anti-angiogenesis therapy, a team of scientists, including USF Health Heart Institute Director Samuel Wickline, MD, investigated the role of the developmentally critical transcription factor Etv2 in tumor angiogenesis. VEGF signaling helps blood vessels survive and maintain stability when disease is not present in addition to regulating tumor angiogenesis. But, Etv2 appears to be expressed only in cancer tissue in adults, making the molecular control mechanism an attractive target, said Dr. Wickline, a professor of cardiovascular sciences and medical engineering at USF Health Morsani College of Medicine.

Findings of the preclinical study, led by Washington University School of Medicine in St. Louis, were reported last year in JCI Insight.

Testing a new target

The researchers found that optimal tumor growth requires reactivation of dormant Etv2, and Etv2-deficient tumor blood vessels resembled normal, stable vessels when mice without tumors were compared to those in which the Etv2 gene was knocked out (disabled). They then injected into tumor-bearing mice nanoparticles carrying small interfering RNA (siRNA) specifically designed to hit and silence Etv2, with the intent of switching off the signaling needed to feed the tumor’s blood supply and fuel VEGF-induced tumor growth.

The treatment worked to block tumor angiogenesis without creating cardiovascular side effects associated with VEGF inhibitors.  More research is needed, but the study authors concluded that combining Etv2 inhibition with chemotherapy or immunotherapy may improve future cancer treatments.

Samuel Wickline, MD, director of the USF Health Heart Institute, and USF Health biomedical engineer Hua Pan, PhD, design nanoparticles to precisely deliver therapeutic molecules to specific cell types associated with inflammatory diseases.

A balance of signals circulating in the microenvironment around each cell tightly regulates angiogenesis.  When no longer needed to establish the cardiovascular system and drive blood supply to the embryo’s developing organs, angiogenesis switches off. In adults, angiogenesis primarily switches on for a limited time to restore blood flow to tissues or organs after injury.  A hallmark of cancer, however, is an angiogenesis switch that never turns off.

“While a tumor (early cancer) is still growing slowly we want to turn off angiogenesis to prevent new blood vessel growth and metastasis,” Dr. Wickline explained. “The idea behind this particular nanotechnology targeting Etv2 is that the treatment selectively inhibits the angiogenesis associated with cancer progression, and not other physiological angiogenesis processes that are needed for repair of tissues anywhere else in the body.”

Potential applications for atherosclerosis

Dr. Wickline’s laboratory built the nanoparticle peptide-siRNA structure capable of precisely delivering a message to silence Etv2 in tumors.  That same nontoxic delivery system can carry other therapeutic molecules to various specific cell types in the body associated with inflammatory diseases, including cardiovascular disorders.

The researchers plan to test whether Etv2 may also be a good nanotherapy target for blocking angiogenesis in atherosclerosis, which leads to fatty plaques building up in the arteries. That’s because abnormal blood vessel growth also provides nutrients to the inflammatory cells inside atherosclerotic plaques and plays a crucial role in plaque rupture that can cause heart attacks and stroke.

“Just like inhibiting angiogenesis starves a tumor of its blood supply,” Dr. Wickline said, “we also want to find ways to starve plaques of the blood supply to keep them from getting bigger and more dangerous.”