The regulation of vascular development and homeostasis is a critical element in the development of cardiovascular disease and protective mechanisms such as adaptive neovascularization
Inflammation is an important component of the host defence reaction against external pathogens and injury, but can also induce and maintain harmful conditions such as atherosclerosis, vasculitis or myocarditis. The endothelial cell layer of blood vessels is a critical modulating structure in this process, as circulating immune cells need to attach to the endothelium and migrate into the vessel wall or the perivascular space to exert their function. In fact, the upregulation of endothelial adhesion molecules due to alterations in fluid shear forces, hypertension or elevated LDL-cholesterol levels is one of the earliest steps in the initiation of atherosclerosis, which is now generally regarded as a chronic inflammatory disease.
Many attempts to modulate leukocyte-endothelial interaction to prevent or reduce excessive inflammatory reactions were made in the past; however, the basic regulatory principles of the endothelial inflammatory process remain little understood. It seems that the inhibition of individual components of the inflammatory cascade, e.g. by a single antibody against an adhesion molecule, may not be enough to achieve a sustained effect on vascular inflammation. Our aim of our research group is identify novel regulators of the vascular inflammatory response to injury and to eventually develop novel anti-inflammatory compounds to treat cardiovascular disease.
The adaptive growth of arteries is an important protective mechanism in patients with vascular occlusive disease. We investigate the molecular mechanisms regulating this process and attempt to stimulate the growth of capillaries and collateral arteries as a possible future therapeutic approach. Angiogenesis (the growth of capillaries) and arteriogenesis (the growth of arteries) involves the complex interactions of different cell types, including endothelial cells, smooth muscle cells and circulating cells, especially infiltrating monocytes and macrophages. Both forms of vascular proliferation can be stimulated by therapeutic substances, especially different cytokines. We have previously identified novel mediators of arteriogenesis and showed that tissue perfusion can be significantly improved by cytokine administration in different animal models.
In close collaboration with the research group of Prof Dr. Martin Moser we are currently pursuing the following projects:
1. MicroRNAs in the vascular system
Recently a new regulatory mechanism that determines gene expression was discovered: MicroRNA (miRNA). miRNAs are short, non-coding regulatory RNAs that regulate protein expression mostly by post-transcriptional repression. miRNAs have been extensively studied in invertebrates, but little is known about their function in mammals. However, recent studies suggest an important role of miRNAs in vascular growth. These small RNAs are currently a main focus of our group and we are pursuing the following projects:
2. Forkhead box transcription factors in vascular disease
The regulation of this angiogenic response to vascular occlusion is a complex event, orchestrated by transcriptional factors that regulate the expression of both pro- and anti-angiogenic genes. Recently, the Forkhead box (Fox) class of transcription factors was implicated in this process. The Fox proteins constitute a large group of transcriptional regulators that are characterized by an evolutionary conserved “winged helix” DNA-binding domain. Currently we are investigating a potential pro-angiogenic, stimulating role of FoxP1 on endothelial cell and vascular smooth muscle cell dependent neovascularization.