Rosenkranz, Stephan - assoc. RG

Cardiovascular diseases (CVDs) remain the leading cause of death worldwide. CVDs are characterized by detrimental remodeling and inflammatory processes in both, heart and vasculature. Within our research group, we are investigating growth factor as well as cytokine driven signaling pathways in CVDs, particular in heart failure with preserved ejection fraction (HFpEF), pulmonary hypertension (PH), abdominal aortic aneurysm (AAA), and atherosclerosis. The focus is primarily on SMCs, but also on leukocytes, cardiomyocytes, fibroblast, and endothelial cells.

HFpEF is an age-related cardiometabolic condition affecting ≈5% of individuals >60 years of age, that is characterized by left ventricular hypertrophy and stiffening, and associated with high morbidity and mortality. Backward transmission of elevated left-sided filling pressure frequently (>80%) leads to PH and consecutive right ventricular (RV) dysfunction. In addition, remodeling of pulmonary vessels contributes to increased RV afterload and dysfunction, and impaired RV–Pulmonary artery coupling. Dependent on the degree of pulmonary vascular impairment, PH in HFpEF is sub-classified into isolated post-capillary PH (IpcPH) and combined post- and pre-capillary PH (CpcPH). We recently established a “three hit” murine model of CpcPH-HFpEF by integrating obesity, hypertension, and hypoxia-induced PH. Taking advantage of this model, we are currently investigating the impact of tumor necrosis factor (TNF) and platelet-derived growth factor (PDGF) on CpcPH-HFpEF.

In addition to PH, vascular remodeling processes play a decisive role in AAA and atherosclerosis. Cell proliferation, migration, and survival promote accumulation of vascular smooth muscle cells (SMCs) in the vessel lumen. The consequences can be a reduced supply of oxygen to the affected organs (ischemia) and subsequent infarction or, in the case of PH, increased afterload and ultimately RV failure. However, in aortic diseases like AAA, characterized by loss of SMCs, proliferation, migration, and survival of SMCs can contribute to aortic regeneration. Thus, signaling pathways involved in SMC accumulation can context-dependently exert detrimental as well as beneficial effects in CVDs. This research focus investigates cellular mechanisms that promotes vascular remodeling processes in PH, AAA, and atherosclerosis. Our data indicates that relevant cellular signal transduction pathways depend on activation of phosphatidylinositol 3'-kinase (PI 3-kinase). Current research therefore focuses on the importance of PI 3-kinase-mediated signals in vascular remodeling in PH, AAA, and atherosclerosis. To this end, PI 3-kinase was inactivated by deletion of various PI 3-kinase isoforms (p110 subunits) in different animal models. We demonstrated that primarily p110a mediates accumulation of SMCs in PH and AAA, whereas p110g and p110d exert inflammatory responses in PH and atherosclerosis, respectively.

For more information about Prof. Rosenkranz´ research and work, please click here. 

• CMMC Center for Molecular Medicine Cologne
• Department III of Internal Medicine
• TRR 259