The research could help identify new drugs or advance tissue regeneration for vascular diseases, including brain aneurysms

Saulius Sumanas, PhD, associate professor of pathology and cell biology, studies the critical regulation of blood vessel formation in health and disease. He joined the USF Health Heart Institute in August 2020. | Photo by Allison Long, USF Health Communications

USF Health’s Saulius Sumanas, PhD, focuses on understanding both normal blood vessel formation and what goes wrong with the critical regulation of these vessels when disease develops.

Arteries and veins and the tiny capillaries connecting them are responsible for transporting blood to organs and tissues throughout the body, among other functions. The molecular factors responsible the growth and health of these blood vessels are important in nearly all diseases.

Dr. Sumanas joined USF Health in August 2020 as an associate professor of pathology and cell biology at the USF Health Heart Institute. He moved his laboratory to Tampa from Cincinnati Children’s Hospital Medical Center and the University of Cincinnati College of Medicine. He says he was attracted by the Heart Institute’s strong cardiovascular research group, with its emphasis on bridging basic science and clinical translational research to create new therapies.

To help define molecular and cellular abnormalities that occur when blood vessels networks do not work as they should, the Sumanas laboratory uses zebrafish to model human diseases, including intracranial (brain) aneurysms associated with cardiovascular risk factors.

“Too little vascular supply can promote some diseases like chronic heart and kidney failure, whereas uncontrolled vascular growth can incite diseases like cancer. For regenerative medicine, the intention is to grow new heart tissue, but there is a simultaneous need to grow new blood vessels to supply nutrients to stem cells that are creating the new heart muscle,” said Samuel Wickline, MD, professor of cardiovascular sciences and director of the USF Health Heart Institute.

“The zebrafish model established by Dr. Sumanas will be a powerful resource to tease out the molecular signals that either need to be enhanced or suppressed to combat these diseases, or to regenerate new functional heart tissue.”

At least 70% of the genes in humans are like those in zebrafish. Zebrafish models, such as the one established by the Sumanas laboratory, can be used to identify molecular signals that need to be enhanced or inhibited to combat diseases, or to regenerate functional heart tissue. | Photo by Allison Long, USF Health Communications

An efficient system for modeling human disease

At least 70% of the genes in humans are like those in zebrafish, and 84% of genes associated with human disease have a zebrafish counterpart.

“The mechanisms regulating vertebrate blood vessel growth are remarkably conserved (across species) from zebrafish to humans,” Dr. Sumanas said. “Even drugs that suppress new blood vessel formation, like the vascular endothelial growth factor (VEGF) inhibitors used to treat tumors in patients, work the same way in zebrafish as they do in humans.”

Other attributes make zebrafish, a member of the minnow family, an efficient model system well suited for scientists searching for genetic clues to disease, including during early blood vessel formation. The fish reproduce and mature rapidly, they are easy to maintain in large numbers for accelerated gene function studies and drug screening, and their eggs are fertilized outside the body. Since zebrafish embryos are virtually transparent, researchers can watch their development in real time. They observe with light and fluorescent microscopy how blood vessels grow from progenitor cells and how the organism’s anatomy and physiology changes when DNA with human genetic mutations is introduced and expressed in the zebrafish.

Ultimately, the Sumanas team hopes to apply what they learn about vascular genetics and developmental biology from this versatile model system to discover new, more targeted treatments for several cardiovascular diseases.

“For example,” Dr. Sumanas said, “now that we have a fish model that shows an increased incidence of hemorrhages (brain bleeds) and defects similar to those of humans with intracranial aneurysms, we can use this model to quickly screen various chemical compounds.” That will help researchers identify if any of the most promising compounds can prevent or reduce the incidence of hemorrhages caused by some intracranial aneurysms. The lead compounds can then be further tested and refined as potential drug candidates for patients.

USF Health’s Saulius Sumanas, PhD, with some of the team members In his laboratory: (L to R) Sanjeeva Metikala, PhD, research associate; Shane Alexander, undergraduate researcher; and Diandra Rufin, biological scientist | Photo by Allison Long, USF Health Communications

Searching for genetic causes of brain aneurysms

While he was a faculty member at Children’s Hospital Medical Center and the University of Cincinnati College of Medicine, Dr. Sumanas collaborated with a group of clinicians looking for genetic variants (mutations) that predispose several members of the same families to intracranial aneurysm, a bulge that forms in a weak area of a blood vessel in the brain. If the aneurysm leaks blood or ruptures, it can cause brain damage and be fatal. (President Joe Biden underwent surgery at age 45, while he was a Delaware senator, to correct a life-threatening brain aneurysm at the base of his brain.)

The Cincinnati group performed functional genomic sequencing of individuals from several families affected by intracranial aneurysms, and subsequently Dr. Sumanas used a zebrafish model to study the functional role of the gene collagen XXII (COL22A1). The researchers demonstrated that COL22A1 plays a role in maintaining blood vessel stability, and their work suggests that mutations in COL22A1 may be a cause of intracranial aneurysms in humans.

Another study led by Dr. Sumanas, reported last year in Nature Communications, discovered that a deficiency of one gene, Etv2, in zebrafish embryos can convert vascular endothelial progenitor cells into skeletal muscle. (Progenitor cells are stem cell descendants that can further differentiate into specialized cell types belonging to the same tissue or organ.) The study concluded that functioning Etv2 actively suppresses these progenitors from differentiating into muscle cells, thereby keeping the cells committed to their vascular destiny: developing into the endothelial cells that are critical building blocks of all blood vessels.

Besides deepening the understanding of complex processes required to differentiate stem cells and grow healthy blood vessels, the work has potential for regenerative therapies, Dr. Sumanas said.

Discovering a gene critical to vascular regulation

Zebrafish embryos are virtually transparent, so researchers can observe blood vessel development in real time. | Image courtesy of Saulius Sumanas, PhD

As a postdoctoral fellow at UCLA in 2006, Dr. Sumanas was the first to identify Etv2 function in forming blood vessels in any organism – and has since studied this gene extensively. “There is a lot of interest in Etv2, because it functions as a master regulator of vascular development and allows you to create vascular endothelial cells in a (petri) dish,” he said. “Eventually, we may be able to grow healthy endothelial cells that could be used to repair damaged blood vessels or contribute to tissue or organ regeneration.”

More research is needed to determine precisely how Etv2-regulated vascular “cell fate” is modified to form skeletal muscle cells, but that too could be clinically useful, Dr. Sumanas said. “It may allow a way to make extra muscle, which could be important for treating different types of muscular dystrophies.”

Dr. Sumanas received his PhD degree in biochemistry, molecular biology, and biophysics from the University of Minnesota. He subsequently completed a postdoctoral fellowship in cell and developmental biology at UCLA. He was a faculty member for 13 years in the Division of Developmental Biology at Cincinnati Children’s Hospital Medical Center/University of Cincinnati before joining USF Health. His awards include a 2004 Vascular Biology Training Grant and a Scholars in Oncologic Molecular Imaging Training Award, both from UCLA; a March of Dimes Basil O’Connor Starter Scholar Research Award; and a Perinatal Institute Pilot Research Award, to name a few.

Dr. Sumanas’ research on the role of collagen COL22A1 in intracranial aneurysms and vascular stability is funded by a four-year $1.8 million grant from the National Institutes of Health’s National Heart, Lung, and Blood Institute. He has published more than 40 peer-reviewed papers in the journals such as Nature Communications, Developmental Cell, Development, Arteriosclerosis, Thrombosis, and Vascular Biology and others. He has served on the NIH Cardiovascular Disease and Differentiation review panel (2021), and as an American Heart Association study section member (2014-2020).

An 11-year-old Saulius Sumanas (left), as he appears in a scene from a 1986 TV miniseries titled “Sesiolikmeciai,” which translates to “Sixteen Year Olds” in Lithuanian. He played a younger version of a teenager appearing in later episodes of the World War II drama.

Something you may not know about Dr. Sumanas

Dr. Sumanas was born in Kaunas, Lithuania. At age 11, he was cast as an actor in the first episode of a dramatic TV mini-series titled “Sesiolikmeciai,” which translates to “Sixteen Year Olds” in Lithuanian. He played the similar-looking, younger boy version of a teenage character who lives through Nazi Germany’s occupation of Lithuania (then the Soviet Union) during World War II.

Dr. Sumanas performed other roles in some amateur theater groups as an undergraduate and postdoctoral student, but his pursuit of a biomedical research career did not waver. “Acting was a lot of fun, but my passion for science was stronger,” he said.

Photo by Allison Long | USF Health Communications