Experimental Vascular and Endovascular Surgery

 About us

The lab is located at the University Hospital Campus nearby the surgical theaters and is embedded in the research lab of the Department of Visceral, Thoracic and Vascular Surgery. Our research aims to understand the role of reactive oxygen species, oxidative stress and biomechanics in the development and progression of abdominal aortic aneurysms and arteriosclerosis in carotid arteries. Another research topic focusses on the development of novel stent technologies for prevention of in‑stent restenosis after endovascular stent placement in peripheral artery disease. Our lab has established a human biobank that contains plasma, serum and tissue samples from more than 800 patients with different vascular diseases. Our research follows a translational aspect and is oriented on patient’s medical needs.

• Abdominal Aortic Aneurysm
• Carotid arteries as a cause of stroke
• New stent technologies in peripheral artery disease

ABDOMINAL AORTIC ANEURYSM

Abdominal aortic aneurysm (AAA) is a common pathology, mainly in males older than 65 years (prevalence: 4-5%). AAA often remain asymptomatic until rupture. In-hospital mortality rates are about 40% and the total mortality rate is ~80%. AAA are characterized by a progressive dilatation of the vessel wall due to inflammation, loss of vascular smooth muscle cells and the disruption of extracellular matrix, that is mainly composed of elastin and collagen. The maximum AAA diameter remains the important clinical surrogate for screening, surveillance and decision for surgery because the risk of rupture increases with AAA diameter. However, the AAA diameter as a predictor for aneurysm rupture has several limitations and there is an unmet need for identification of other markers reflecting the growth rate or the risk for rupture. Small AAA are treated conservatively and by regular monitoring of the AAA diameter. The therapeutic indication for surgical removal is set at a diameter of >55 mm.  Development of novel non-surgical therapeutic options, requires a detailed understanding of the molecular mechanisms that contribute to initiation, progression and AAA rupture. Our specific aim is to understand the physiological and pathological impact of reactive oxygen species (ROS) on mechanism contributing to AAA progression and rupture. ROS are produced by inflammatory and vascular cells (endothelial cells, vascular smooth muscle cells, adventitial fibroblasts) and basal levels are required for maintaining cell growth, cell death, migration, inflammation, and extracellular matrix production. Targeting ROS-releasing enzymes or molecular pathways that are involved in ROS production and the identification of ROS-modified molecules are promising treatment strategies in cardiovascular disease but need evaluation in AAA.
Other studies focus on biomechanics and mechanobiology in progression and rupture of AAA. The intramural wall stress caused by the blood pressure is an important determinant in AAA progression and rupture. In AAA rupture, the wall stress exceeds the vessel wall strength. The complex interaction between mechanical forces, cells in the vasculature and the extracellular matrix is poorly understood. Our studies focus on biomechanical forces (e.g. shear stress) and their effects on smooth muscle and endothelial cells, extracellular matrix components, contractile proteins and signaling molecules. We aim to identify cellular and molecular mechanisms that are affected by mechanical forces and are linked to AAA rupture. Our aim is to connect findings at the tissue level to the patient’s clinical data (e.g. AAA diameter, imaging) to assess AAA at high risk for rupture.

Human aortic smooth muscle cells isolated from an human abdominal aortic aneurysm. A) Aged HuAoSMC, B and C, staining of smooth muscle cell markers by immunofluorescence.

All our studies utilizes patient blood, human aortic tissue samples, primary cell cultures and preclinical experimental animal models to study underlying mechanisms and to develop novel treatment strategies to slow or stop the progression of the disease.

CAROTID ARTERIES AS A CAUSE OF STROKE

Around 15% of all ischemic strokes are due to a progressive narrowing or occlusion of internal carotid arteries. The narrowing is caused by atherosclerotic plaques that reduce or completely block the blood flow and oxygen supply to the brain. Furthermore, plaque rupture and the release of plaque material can cause brain ischemia due to occlusion of smaller, peripheral arteries. In early stages, proliferation and migration of vascular smooth muscle cells (VSMC), secretion of extracellular matrix and lipid accumulation is typical and promotes the thickening of the lesion. In advanced lesions, a necrotic core with lipids, lipoproteins, calcium, thrombogenic material and inflammatory cells is covered by a fibrous cap, composed of collagen. Thinning of the fibrous cap causes plaque rupture. Inflammatory cytokines, ROS and matrix-degrading enzymes contribute to the degeneration of the fibrous cap. Stabilization of advanced plaques represents one mechanism in treatment of asymptomatic patients prior they become symptomatic. Our aim is to identify mechanisms that contribute to the stabilization and destabilization of vulnerable arteriosclerotic plaques in carotid arteries. Our research focusses on NAD(P)H oxidases (NOX) and oxidative stress in VSMC, as the sole cell type in the thickening, but also thinning, of the fibrous cap. Our research focusses on NOX4, an ROS-generating enzyme that is expressed by nearly all cells in the vasculature. Contrary to other NOX enzymes, NOX4 is the only enzyme generating superoxide anion radicals (◦O2-) and hydrogen peroxide (H2O2). In low doses, H2O2 acts as an intracellular messenger and is required as a signaling molecule, playing an essential role in cellular processes like migration and proliferation. H2O2 can alter the activity and function of proteins by inducing modifications of cysteine residues. Our research hypothesis proposed that NOX4 and NOX4-derived H2O2 promote a stable plaque phenotype. Our research is conducted in human arteriosclerotic plaques and in plaque-derived primary VSMC obtained from patients with asymptomatic and symptomatic carotid artery stenosis. We isolate VSMC by using the explanation technique to obtain cells in the synthetic state and by enzymatic digestion to work with contractile VSMC.

Arteriosclerotic plaque obtained from a patient with carotid artery stenosis. Left: Staining for alpha-smooth muscle actin and right: Elastica-van-Gieson for staining elastic fibers.

NEW STENT TECHNOLOGIES IN PERIPHERAL ARTERY DISEAESE

In-stent restenosis (ISR) is a common problem after endovascular stent placement in surgical treatment of peripheral artery disease (PAD). Placing endovascular stents injures the vessel wall, especially endothelial cells in the inner layer of blood vessels. The healing response involves platelet adhesion, and secretion of chemokines and mitogens by activated endothelial and immune cells. These factors stimulate the migration and proliferation of vascular smooth muscle cells and the secretion of collagen fibers in the extracellular matrix, leading to neointimal hyperplasia. The major clinical problem of ISR is the decrease in the overall technical success rates and the medical need for second, surgical revascularization procedure. Further important issues that have to be addressed during development of novel stent materials are: 1) improving endothelial cell revascularization, 2) minimizing hypersensitivity reactions, 3) avoiding destruction of the stent material and 4) providing a fully bioresorbable scaffold.  To address all these requirements, an intensive collaboration between materials sciences, medicine at the bedside and experimental basic science is required. Our research focuses on the basic science part in testing the cellular toxicity and hemocompatibility of the novel stent materials. Our lab is analyzing the cellular mechanisms contributing to ISR in VSMC as it shows similarities with atherosclerotic processes. We are establishing explanation techniques and long-term culture of atherosclerotic plaques from patients with PAD to assess their interaction with novel stent coatings and material. Using primary VSMC from patients with PAD enables us to analyze the process of ISR in the setting of pre-existing atherosclerotic changes in the vessel wall.