Cardiovascular science as social network

There is strength in numbers, and in unity, as members of the Yale Cardiovascular Research Center (YCVRC) know. Less than a year after moving into new laboratory space expressly designed to foster collaboration and shared resources, the 16-person team, led by YCVRC Director Michael Simons, M.D., has received a $9.5 million five-year Program Project Grant (PPG) from the National Heart, Lung, and Blood Institute, a component of the National Institutes of Health. The grant will support research on the molecular basis of arteriogenesis—the process by which new arterial blood vessels are formed—with the aim of developing a new framework for drug discovery and other therapeutic advances.

Since his arrival at Yale from Dartmouth Medical School in 2008, Simons, a leading researcher on the role of arteriogenesis in cardiovascular diseases, has created a unique scientific climate at the YCVRC that has attracted top scientists he describes as “stars.” In turn, the expansion and diversification of YCVRC faculty has opened up new research directions and new avenues of funding. The new PPG is a concrete recognition of the unusually complementary and interrelated research projects happening at the YCVRC, says Simons, the Robert W. Berliner Professor of Medicine, professor of cell biology, and chief of the Section of Cardiovascular Medicine. It reflects an upward spiral in cardiovascular research at Yale—research that may lead to new arteriogenic therapies for illnesses like atherosclerosis, in which buildup of cholesterol and fatty materials causes an artery wall to thicken, and metabolic syndrome, a combination of medical disorders that can jointly lead to cardiovascular disease and diabetes. “This would not have happened three years ago,” he says, “because we would not have had the people.”

Scientific diversity

One of the YCVRC team’s greatest strengths is its scientific diversity. For instance, Martin A. Schwartz, Ph.D., professor of medicine and cell biology, is an expert in the way “fluid shear stress,” the friction of flowing blood against the endothelium (cells that line all blood vessels), regulates their behavior. As part of the new PPG, Schwartz’s lab will study how increased flow leads to the growth of new arteries. Recruited to Yale in 2011 from the University of Virginia, Schwartz is one of the newest members of the YCVRC and the PPG team.

Shear stress, Schwartz explains, is “the critical stimulus” in the formation of collateral arteries that grow around blocked arteries, a kind of natural bypass. Following the occurrence of an arterial blockage, as happens in a heart attack, for example, “some people can make these collateral arteries pretty efficiently, and some people don’t,” he says. The making of these collateral arteries is critical to recovery. For more than 10 years, Schwartz has investigated the mechanisms underlying this phenomenon experimentally, and he has made real progress. “We’re now at the point where we can apply our understanding to the problem of flow-dependent artery remodeling” in human patients.

Anne Eichmann, Ph.D., M.Sc., professor of medicine, was recruited to the Center in 2010 from the Collège de France. Eichmann studies the factors that determine where the cells in blood vessels and lymphatic vessels grow. “We know about the factors that tell endothelial cells how to grow, but we’re much less familiar with the cues that tell them where to grow,” she says.

Among Eichmann’s other areas of interest is neurovascular biology—specifically, to understand how the vascular and nervous systems influence each other’s growth and function. The vascular and nervous systems appear to be more closely related than previously thought: “In multicellular organisms,” Simons explains, “the nervous system evolved first, and the vascular system followed, and it’s beginning to look like they used the same set of molecules.” This connection holds tremendous potential for biomedical research, says Simons. “It turns out that the vasculature controls the function of the nervous system, and the nervous system controls the function of the vasculature. There’s a huge overlap between neurobiology and vascular biology, and we’re trying to build a program that takes advantage of the expertise Yale has in those fields.”

Eichmann has explored the effects of the interactions between nerves and arteries on blood pressure; and another recent recruit, Jean-Léon Thomas, Ph.D., M.Sc., associate professor of neurology, has pursued research on the relationship between vasculature and brain function. In 2011, Thomas, Eichmann, and colleagues reported in the journal Genes & Development that they had identified stem cells in the brain that replace damaged nervous tissue, and that a protein called vascular endothelial growth factor (VEGF) receptor 3 acts directly in these stem cells to stimulate the creation of new nerve cells in adults—findings that have implications for neurodegenerative diseases such as Alzheimer’s and Parkinson’s.

Another recent addition to the YCVRC is Karen K. Hirschi, Ph.D., professor of cardiology, who joined the faculty in the fall of 2011. Hirschi studies signaling pathways that regulate endothelial cell differentiation, specialization, and growth during early vascular development. Her lab is also using this basic biological information to direct the fate of human pluripotent stem cells (both embryonic and induced), which can become any cell type, specifically toward vascular cells. Hirschi’s aim is to understand how to get human stem cells to efficiently become vascular endothelial cells, so they can be used to form new blood vessels in regenerative medicine strategies.

Other recent recruits include Daniela C. Tirziu, Ph.D., instructor in medicine, who specializes in cell-to-cell communications in the heart; Daniel Greif, M.D., assistant professor of medicine, who works on pulmonary artery development and function; Hyung Chun, M.D., assistant professor of medicine, whose interests include pulmonary hypertension; Suk-Won Jin, Ph.D., and Stefania Nicoli, Ph.D., both assistant professors of medicine who use zebrafish as a research model; John Hwa, M.D., Ph.D., associate professor of medicine; Kathleen Martin, Ph.D., associate professor of medicine; Daniel L. Dries, M.D., M.P.H., associate professor of medicine and medical director of the Yale Center for Advanced Heart Failure; and Yibing Qyang, Ph.D., assistant professor of medicine and of pathology. Qyang, like Hirschi, studies stem cells—particularly cardiovascular progenitor cells (CPCs), which are capable of making nearly an entire heart during formation—and is working to better understand the biology of CPCs with the aim of developing and enhancing therapies for disease and injury.

Abundant resources

Since Simons’ arrival in 2008, grant funding for cardiovascular research at Yale has nearly tripled, increasing from about $8.5 million to about $24 million in 2012. This amount includes a five-year $6 million grant from the Paris-based Fondation Leducq under the auspices of its Transatlantic Networks of Excellence in Cardiovascular and Neurovascular Research program, awarded in 2010. The School of Medicine, at which the Leducq grant is supporting YCVRC research on the link between arteriogenesis and metabolism, is one of just six research institutions taking part in this international project, which is built around frequent and close communication.

But it’s not simply funding that has enticed leading cardiovascular researchers to set up shop at the School of Medicine. Another crucial factor is the “unique environment” of the YCVRC, Simons says, a collegial place where “everybody has a say. People help each other, and we have several fantastic interaction forums.” These include a weekly faculty gathering held in a purpose-built lunchroom in the center’s suite at 300 George Street (see photo). “If you’re there, you could be asked to talk off the cuff about what you do,” Simons explains. “All our joint funding has come out of this faculty lunch.”

Cardiovascular medicine is a scientific success story, as research has led to effective medications to manage cholesterol as well as angioplasty and stents, which allow doctors to widen narrow or blocked blood vessels. “But there has never been a medication that changes the nature of disease,” Simons says. “All the currently available treatments—and they’re very good—do not address the underlying biology of disease, and they basically palliate. The question is: how can you understand what’s going on?”

Collaboration

YCVRC members collaborate very closely with other groups at the medical school. One notable relationship is that between the YCVRC and the Vascular Biology and Therapeutics (VBT) Program. Formed in 2000, VBT was the medical school’s first interdepartmental research program explicitly focused on translating laboratory discoveries into practical treatments for disease. Now led by William C. Sessa, Ph.D., the Alfred Gilman Professor of Pharmacology, VBT’s diverse and collaborative design served as a model for the YCVRC, and functions as its “sister” program.

VBT members meet with YCVRC scientists in regular joint lab meetings. A leading researcher on blood vessel function and vascular disease, Sessa is one of the new PPG’s seven investigators. The others are Tirziu; Simons; Schwartz; Themis Kyriakides, Ph.D., associate professor of pathology and of biomedical engineering; Laura E. Niklason, M.D., Ph.D., professor of anesthesiology and of biomedical engineering, a pioneer in tissue engineering; and Albert J. Sinusas, M.D., professor of medicine and of diagnostic radiology, a YCVRC member and an expert in advanced cardiovascular and molecular imaging. All seven scientists are members of VBT.

“We see VBT and the YCVRC as a single program, because people interact so effectively—at seminars and retreats, and at joint lab meetings,” Sessa says. “There are common research interests, and everyone is secure enough with their own work to champion collaborative interactions. Michael Simons’ recruitment gave us a partner in cardiology to synergize with.”

Other budding YCVRC collaborations involve the Departments of Neurology, Ophthalmology, and Psychiatry. Each month, YCVRC scientists convene with colleagues from the Department of Neurology at a neurovascular meeting to explore the implications of vascular research in the brain. For instance, Jaime Grutzendler, M.D., associate professor of neurology and of neurobiology, studies the brain’s microvasculature

—its smallest blood vessels—and is interested in “vascular dementia,” or the ways neurovascular defects contribute to cognitive decline in the elderly. The expertise of YCVRC scientists like Eichmann, Hirschi, and Thomas, who all work in areas related to neuroscience, is something Grutzendler is now able to tap into.

Ophthalmology is closely linked to neurovascular research, says Hirschi, because “the retina is a neural tissue. Several of us in the YCVRC are interested in ophthalmological disorders that occur because of dysregulated blood vessel formation—or [as with diseases like “wet” macular degeneration], when there’s an overgrowth of blood vessels in the eye that inhibits vision.”

In May, the YCVRC and VBT will convene an international neurovascular symposium in New Haven jointly with University College London (UCL) scientists, many of whom “work on [neurovascular interactions and] eye disease,” Hirschi says. “We hope to form collaborations so that we can do studies for eye disease [similar to our studies on the neurovasculature of the brain].”

In the area of psychiatry, too, there is much overlap. Thomas, for instance, studies the effects of VEGF signaling on behavior, and is working jointly with colleagues in the Department of Psychiatry to gauge the links between VEGF and behavioral outcomes like depression and anxiety.

“The symposium enables everyone to share his or her work, get a feel for what everyone else is doing, and identify mutual interests on which we can build joint research programs and training opportunities,” Hirschi says.

Scientists from Yale and UCL are also collaborating on a project recently funded by a European Community (EC) grant, administered by the European Union. Sinusas, Tarek Fahmy, Ph.D., associate professor of biomedical engineering, Simons, and Niklason are working jointly with colleagues at UCL, with U.K.-based Ark Therapeutics, and also with teams of scientists in Germany and Finland, to design and test a new technology designed to improve healing around implanted vascular stents. The technology involves using magnetized biodegradable stents, which will attract stem cells that have been loaded with iron particles; and, additionally, stents in which viral vectors have been embedded, to promote the adhesion of stem cells. The aim of the new technology—which the scientists hope will be tested in human patients within four years—is to alleviate circulatory problems arising from obstructive blood clots and narrowed blood vessels in patients with coronary stents.

The four-year $4.5 million grant is the first EC grant to fund the work of American scientists, Simons says, and could not have been possible without the existence of the Yale UCL Collaborative, which was created in 2010. “This grant is unique in that it brings together several biotech companies and academic institutions that have complementary expertise,” Sinusas says.

Thanks to advances in genome sequencing technologies, and in particular to state-of-the-art genetic screening capabilities now offered by the Yale Center for Genome Analysis, YCVRC scientists are increasingly able to rely on genetic analyses of individual patients in conducting basic research—with the hope that this research can then be brought “back to the bedside” as therapy for disease. Cardiovascular genetics efforts at the YCVRC, led by Arya Mani, M.D., associate professor of medicine and of genetics, working together with colleagues from UCL and Yale’s Department of Genetics, have already resulted in “significant new insights in our understanding of early atherosclerosis and metabolic syndrome,” Simons says.

Scientists have traditionally believed that cardiovascular illnesses are caused by numerous small changes in many genes. But “it appears now that there are a number of genes in which a single mutation will give you a significant phenotype,” Simons says—which increases the odds that scientists can identify the gene variants that cause a particular disease, understand that disease’s biology, and find new therapies.