The health problem
Cardiovascular diseases and their associated complications like stroke, heart failure or organ dysfunction currently account for 40% of deaths and impact significantly on costly long-term health care. This is a world-wide trend that is increasing at an alarming rate in European countries. Cardiovascular diseases are commonly associated with large vessel atherosclerosis; however, there is accumulating evidence that major disturbances occur in the small arteries. Our body contains millions of these tiny vessels, thinner than a human hair. They control how much blood is transported to each and every corner of our body. Failure of these vessels occurs in response to hypertension, aging, diabetes, obesity, and a sedentary life style. The consequences include cognitive decline, heart failure and kidney failure, and aggravation of hypertension in a vicious circle with a major risk for acute events, notably stroke and myocardial infarction. Yet, treatment options targeting our small arteries are very limited. These vessels have literally been overlooked over the years, and scientific understanding of their dysfunction is lagging. There is much to gain here!
Importance of small arteries
Our systemic arteries branch from the large aorta to increasingly smaller vessels, ending in the capillary bed that allows perfusion and oxygenation of all tissue in the body. This is an amazingly large network, containing hundreds of millions of blood vessel segments. Their diameter varies from 25 mm in the aorta to 0.01 mm in the most distal segments. In order to maintain blood flow through this network, a driving pressure is needed, which is the blood pressure generated by the heart. The ratio of pressure and flow is the resistance of this network. It turns out that vessels with diameters of around 0.2 mm and smaller contribute to this resistance. Hence these vessels are called resistance arteries or small arteries. You cannot easily see them (on MRI or CT) or feel them (from the pulse). Yet they are there and they form the very vast majority of the arterial segments. The small arteries have a very important task: to regulate local blood flow in each and every corner of our body. They do so by adjustments of their diameter. Quick functional changes occur within seconds and are accomplished by contraction and relaxation of smooth muscle cells in the wall. Chronic changes in diameter result from reshaping of the vascular wall, where existing elements are reorganized, new elements are added or elements are broken down. We call this vascular remodeling. The regulation of arterial diameter and wall structure is a continuous process of adaptation to changing needs, ranging from exercise to development of the body. This adaptation may malfunction: too small a diameter of the resistance vessels relates to insufficient tissue perfusion as well as hypertension. The vascular wall consists of among others the vascular smooth muscle cells, endothelial cells that line the lumen, and elastic fibers and other extracellular matrix elements. Physical forces form an important part of the adaptation mechanisms of small arteries: Blood pressure causes distension of the matrix elements, but also induces contraction of the smooth muscle cells and production of more cells and more matrix. Blood flow is sensed by the endothelial cells, which release factors such as nitric oxide that cause relaxation and remodeling towards larger diameters. Forces, cells and matrix therefore form a triangle of mutual effects that underlie vascular adaptation. We worked on unraveling the functioning of this triangle.
Our SmArteR consortium
The SmArteR group consists of European academic institutes and enterprises who perform R&D in the field of small arteries. You will find us at www.smallartery.eu We aim to improve scientific understanding of the role of these blood vessels in cardiovascular disease, to pave the way for new therapeutic options, and to train young scientists in this field. SmArteR was financially supported by the Marie Curie programme of the European Commission between November 2013 and January 2018 and is currently evolving into a larger network on the basis of new grant applications.
The work that we performed in SmArteR
We studied small arteries on all levels of biological integration:
We studied molecular pathways in the vascular cells that may form the basis for future drugs. This work concentrated on so-called transcription factors, molecules in the cells that regulate the expression of genes. We were particularly interested in transcription factors that are activated by forces in the wall, related to a high blood pressure. We further studied parts of the vascular matrix. In this work we identified several key molecular players in small artery remodeling and obtained information on their mechanisms of action. The work has been communicated mainly by scientific papers and should provide the scientific community and pharma industry with several new leads for future research and product.
Our work on vascular cells included the endothelial cells and smooth muscle cells (the ‘sensor’ and the ‘motor’ of blood vessels) but also considered the role of stem cells. We identified how sensing the forces and responding to them is affected in diseased vessels. This work also revealed that interaction of endothelial and smooth muscle cells with blood on the inner side and other cells on the outer side is a crucial element in vascular remodelling. These complex interactions are only beginning to be understood, but make clear that a still more integrative approach is needed for studying cellular behavior in and around the vascular wall.
Part of our work considered the small artery as a whole, aiming to include many of the above processes. As an example, we investigated the expression of all genes in vessels from animals that had high blood pressure. This ‘fishing expedition’ provided many new candidates that were partly studied in SmArteR and are partly studied in future consortia or by other groups. In this work, we stumbled on new roles for the small arteries beyond their blood transport function. Thus, it became clear that the active transport of water from the lumen of the vessels to the tissue is strongly affected in the hypertensive brain.
SmArteR united academic and entrepreneurial partners, and part of the work was dedicated to new technology. This work focused on the very dedicated technology that is needed to study these vessels and delivered platforms for such study that can be invoked by e.g. the pharma industry.
SmArteR has produced a vast array of studies in well-established scientific journals. In the process, 15 young investigators were trained in the lab and during several network events to become independent researchers and will promote and extent the field. The 12 Ph.D. students all obtained or are obtaining their Ph.D. degree, while the 3 post-docs are pursuing their industrial careers based on their experience within the participating small-medium enterprises. As PI’s and fellows, we generated a network of research groups that will continue to collaborate on these small but so important arteries.