The First EVGN Annual Conference: Scientists Describe A Potential Vaccine Against Heart Disease

What is the relationship between atherosclerosis and the immune response and what are the possibilities for the development of a vaccine against cardiovascular disease? What role do stem cells play in angiogenesis and what are the possible clinical applications of stems cells in cardiac recovery?

These are few of the topics that will be discussed during the First European Vascular Genomics Network (EVGN) Conference, which starts today at New Hall College in Cambridge, UK. Chaired by British Heart Foundation Professor Andrew Newby (Bristol, UK), 140 vascular biologists drawn from the 35 EVGN networked laboratories and from the wider scientific community are taking part. “Some of Europe’s most eminent vascular biologists are holding a series of plenary lectures,” Newby says. “Perhaps more importantly, however, there is a unique series of highly focussed workshops, each of which is designed to reach a consensus on future approaches to key areas of strategic scientific importance.” EVGN, a Network of Excellence funded by the European Union within its Framework Programme Six, was implemented on January 1st, 2004. “Consonant with the overall aims of Framework Programme Six, the EVGN in general and the Conference in particular will also give emphasis to wider social issues such as gender equality, communication of scientific progress to the general public and maximising the exploitation of scientific breakthroughs through both large and small enterprises,” Newby adds.

EVGN promotes multidisciplinary interaction in the field of vascular biology by uniting 25 basic and clinical institutions (encompassing 35 academic groups), 2 biotechnology companies and 1 management company, from 10 EU Member or Associated States. “The Conference will allow presentation and intensive discussion of frontier research in vascular biology, in an effort to integrate research activities of all groups from the EVGN,” says EVGN scientific coordinator Alain Tedgui, of INSERM (Institut National de la Santé et de la Recherche Médicale, Paris, France). “The attendees will present their latest results pertaining to the three research focus areas of the EVGN: endothelial dysfunction, atherosclerotic plaque rupture and therapeutic angiogenesis. Furthermore, state-of-the-art lectures will be presented by worldwide recognized experts, on clinical perspectives of these three main research areas”.

The First Year’s Results

The EVGN struggle against cardiovascular disease is fought mainly on “post-genomic ground”. By identifying and analysing the genes and proteins – and their complex relationships – that are responsible for the onset of the diseases, it will be possible to develop new effective drugs and therapies and new tools and methods of diagnosis. To do so, EVGN can count on powerful human and technological resources. “We have combined resources and expertise to examine human arteries and material from model systems and we have established state-of-the-art facilities and expertise with standardized protocols and bioinformatics,” EVGN scientist Martin Bennett, of the Division of Cardiovascular Medicine at the University of Cambridge (UK), says. “The first target genes have already been identified using both genomic and proteomic screens and we have also established the model system required to study their role in the cause of heart attack”.

Clinical Trials On Therapeutic Angiogenesis And Stem Cells

Is it possible to improve cardiac recovery by enhancing the process of vessel growth? To test this possibility, EVGN scientists in Frankfurt and Homburg are now carrying out clinical multi-centre trials on patients with acute myocardial infarction. “We have started clinical trials to use the so called ‘Endothelial Progenitor Cells’ to enhance vessel formation: this is an entirely new concept and represents the most innovative aspect in the research area of stem cells and therapeutic angiogenesis,” EVGN scientist Stefanie Dimmeler, of the University of Frankfurt (Germany), says.

Angiogenesis (from the Greek angêion = “vase”, and genesis = “birth”) is the science that studies the formation of new vessels. Among its therapeutic applications, aimed at improving cardiac oxygenation and reducing heart failure, innovative methodologies have been recently developed using Endothelial Progenitor Cells (EPC). These adult stem cells, made in the bone marrow, can differentiate into cells of the endothelium and may directly participate to the angiogenic process. In collaboration with other EVGN laboratories, Dimmeler set out to characterise this mechanism. “We don’t know how EPC are regulated in patients and we want to understand how they can differentiate into endothelial cells to form new blood vessels,” Dimmeler says. ”The EVGN laboratories are now sampling 500 volunteers to characterise their EPC. By comparing the results obtained in both healthy individuals and patients with heart failure, and by combining this study with our previous knowledge on embryonic stem cells by the expert laboratory of Elisabetta Dejana, of the FIRC Institute of Molecular Oncology (Milano, Italy), we might be able to enhance the process of vessel growth. Preliminary results show that patients with coronary artery disease have less EPC than healthy volunteers.”

Identification Of Molecular Targets In Endothelial Dysfunction

The endothelium is a thin layer of flat smooth cells that line the inner walls of blood vessels. The term “endothelial dysfunction” reflects a state of endothelial cell activation in which, for example, blood flow-induced changes in vessel diameter are attenuated and the expression of a number of pro-inflammatory proteins is enhanced. Since this state is key to the atherosclerosis progression, the endothelium can be seen as an early therapeutic target, and the maintenance of normal endothelial cell function would be expected to delay the vascular inflammation associated with clinical symptoms. But the mechanisms resulting in endothelial dysfunction have yet to be fully characterised. “We know for example that the very same stimuli that elicit an increase in blood flow in a healthy vessel do quite the opposite during the development of atherosclerosis. Our goal is to determine why and how the functions of the endothelial cells change during the atherosclerotic process,” EVGN scientist Ingrid Fleming, of the University of Frankfurt (Germany), says. “The idea is to find critical molecular targets that could then become therapeutic ones. Many of our partner laboratories are actively involved in the identification and characterisation of the proteins that play a crucial role in endothelial dysfunction. A particularly important emphasis is being placed on identifying enzymes within the blood vessel wall that generate ‘free radicals’ [highly reactive molecules that can damage and destroy the cell structures] which previous studies have found to be connected with the dysfunction.

One of the main objectives of EVGN in this area is to develop and implement new standardised protocols for target identification, to be applied in all European laboratories. “We are currently using a quite advanced technique, that combines biochemistry and in vivo experiments in animal models,” Fleming says, “Thanks to this highly efficient technique, we hope to be able to gather a lot of information in a limited amount of time.”

Immune Responses Discovered In Atherosclerosis May Be Used To Develop A Vaccine Against Heart Disease

The laboratory of Göran K. Hansson, at Karolinska Institutet (Stockholm, Sweden) is contributing to the EVGN research activities on the double frontline of atherosclerosis therapy and prevention. Atherosclerosis, the hardening of the arteries caused by accumulation of fatty deposits (plaques) and other substances, is the main cause of arterial thrombus (blood clot) formation, coronary artery occlusion and heart attack. But scientists have found a weak point in this too often lethal disease: atherosclerosis is an inflammatory process and as such could be treated. “Several research groups in Europe and in the United States have reported that immune responses are involved in atherosclerosis,” Hansson says. “However, only now it has been realized that the inflammation elicited by the atherosclerotic plaque is the key factor that will eventually precipitate thrombosis and infarction.”

Hansson has studied patients with atherosclerosis and identified T cells (immune cells) that recognize cholesterol particles (lipoproteins). “Oxidation of these lipoproteins in the blood vessels causes chemical changes in the particles, which are now recognized by the immune system as if they were pathogenic microbes. We have found that immunization of experimental mice with oxidized lipoproteins protects the animals against the development of atherosclerosis,” Hansson explains. “This may open up a new possibility to prevent heart attacks and stroke by vaccination.”

On the therapy frontline, Hansson is currently studying the mechanisms that regulate the immune response to atherosclerosis. “Working together with the EVGN team lead by Alain Tedgui, in Paris, we have observed that activated immune cells can produce signal molecules, called ‘cytokines’, that dampen the atherosclerotic process, Hansson adds. “These molecules might be very interesting targets for future therapy, to reduce the risk of stroke. There is a lot to learn, but we are on our way and our preliminary results are promising.”

Vascular Biology In Europe: The Key Role Of EVGN

Vascular Biology is the basic science discipline that underpins increased understanding and new treatments for coronary heart disease, stroke and other cardiovascular diseases. “These collectively account for more deaths in people of working age than any other group of diseases,” Conference chairman Andrew Newby explains. “Moreover Vascular Biology makes an important contribution to understanding the growth of tumours, which like all tissues need an adequate blood supply.” Hence Vascular Biology also plays a relevant role in the study of cancer, the other major killer of younger people. And there is more: “Vascular Biology is the scientific basis for much of the biotechnology and pharmaceutical industry activity related to these diseases and hence an important contributor to wealth creation in this sector, as well as health, in Europe,” Newby adds.

Despite its importance, Vascular Biology has lacked a collective voice at European level. “This has happened,” Newby explains, “partly because the discipline is bigger than one disease area. Vascular Biology is also farther from the ‘market’ than areas such as Cardiology, Radiology and Diabetology, for example, all of which have powerful European professional organisations funded for the most part by firms that service these clinical activities.”

In recognition of these limitations, part of the brief of the EVGN is to permanently restructure the field of Vascular Biology in Europe. EVGN is working with established groups such as the European Vascular Biology Organisation to make the leap to democratically representing the interests and aspirations of European vascular biologists. In its first year, the EVGN has built a Web based communication platform and undertaken detailed planning for the first summer school, to take place in 2005. In addition, it is directly funded to establish a wider communications network among vascular biologists, a summer school for young vascular biologists in training, and a series of European Vascular Biology Research Conferences.