Research project P5/02 (Research action P5)
The formation of blood vessels, key players in health and numerous disorders, requires the growth of endothelial cells ("angiogenesis"), smooth muscle cells ("arteriogenesis") and vascular stem cells ("vasculogenesis"). Proteolytic systems, such as the plasminogen activator (PA) and matrix metalloproteinase (MMP) systems, and vascular endothelial growth factor (VEGF)-family members, play a central role. Endothelial cells also determine the function of their peri-endothelial cells, such as the cardiomyocytes in the heart. Since vascular perfusion is not only improved by increased formation of new vessels but also by enhanced perfusion (dependent on cardiac function), it is essential to study this process. Furthermore, purinergic P2Y receptors contribute to signalling in endothelial cells. In the present proposal, we will study the role of these molecules in more detail.
Atherosclerosis is the underlying pathology of cardiovascular disease, which is responsible for 40% of the mortality in the Western society. Early atherosclerotic lesions are fatty streaks consisting of foam cells. These lipid-laden cells develop through the uncontrolled uptake of oxidised low-density lipoproteins (oxLDL). Subsequently these lesions may develop into atheromatous plaques, with a necrotic core covered by a fibrous cap. This cap is composed of extracellular matrix produced by smooth muscle cells (SMC). It contributes to the stability of the lesion. Weakening of the fibrous cap by macrophage infiltration, extracellular matrix degradation and SMC apoptosis increases the risk of plaque rupture and subsequent atherothrombotic complications. Initially, adaptive remodelling compensates for plaque growth. Macrophage accumulation, matrix degradation and apoptosis lead however to constrictive remodelling and thus to loss of lumen (stenosis).
Percutaneous transluminal angioplasty (PTCA) is essential in the treatment of coronary stenosis. However, PTCA associated restenosis and stent related neointima formation represent major limitations of this procedure. The mechanisms underlying these processes are poorly understood, partly because of the lack of representative animal models.
The main objectives of this program are to study the role of several master genes of angiogenesis and arteriogenesis in cancer, retinopathy, myocardial ischemia and obesity, and to study the relations between oxidative stress, inflammation, ischemia and atherothrombosis. Specific objectives include: study of the role of VEGF homologues and receptors in (patho)physiological angiogenesis; role of proteinases in angiogenesis in obesity and cancer; mechanisms of endothelial and endocardial cell signalling; relation metabolic syndrome, oxidation of LDL and coronary atherosclerosis; effect of oxidative stress on differential gene expression in endothelial cells; effect of hypercholesterolemia on in vivo differential gene expression in mice in relation to endothelial cell and cardiomyocyte function; effect of gene therapy of high-density lipoprotein related genes on atherosclerosis and heart function in mice.
To achieve these goals, we will use the most advanced state-of-the-art gene technologies including gene-discovery (µ-arrays), gene manipulation (knockout and knockin transgenic mice) and adenoviral and non-viral gene transfer in combination with extensive use of in vitro and in vivo models.
