The interplay between hemodynamic forces and inflammatory processes in the development and destabilization of atherosclerotic plaque

• Applicant: Professorin Iwona Cicha, Ph.D.
• Subject Area: Cardiology, Angiology
• Term: from 2008 to 2012
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 61703388

Atherosclerotic plaque formation results from a combination of local blood flow patterns and inflammatory processes. This project focuses on the impact of hemodynamic forces in combination with inflammatory agonists on the development, progression, and destabilization of atherosclerotic lesions, and on the therapeutical possibilities of pharmacological modulation of these processes. 1. Using bifurcating flow-through cell culture slides we will expose endothelial cells to laminar or non-uniform shear stress at arterial level, in order to analyze important endothelial functions, such as release of cytokines/chemokines and recruitment of leukocytes under specific flow conditions, in the presence or absence of inflammatory agonists. 2. We will subsequently investigate the rolling and adhesion of leukocytes to arterial bifurcations in vivo using intravital microscopy. First, we will compare straight artery regions to vessel bifurcations in healthy animals, and subsequently we will investigate the regional differences in leukocyte recruitment between upstream and downstream regions of the plaques in ApoE/LDL receptor double-knockout mice (ApoE-/LDLR-). 3. The mechanisms of plaque formation and destabilization in relation to local flow patterns and vessel geometry will be investigated on a large number of longitudinal sections of advanced human carotid lesions and of pre-atheroma carotid specimens from victims of accidents. Moreover, the magnitude of inflammatory processes in upstream versus downstream regions of the plaques will be analyzed within an ongoing study regarding metabolic and structural plaque characterization by PET/CT. We believe that the results of the planned study will improve the understanding of flow-mediated processes in pathophysiology of atherosclerosis and will contribute to more precise pharmacological targeting of atherogenesis-related endothelial dysfunction and plaque destabilization.

• DFG Programme: Research Grants
• Participating Person: Professor Dr. Christoph Dietrich Garlichs