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Introduction: Calpain-1 and Calpain-2 are acute phase proteins involved in proinflammatory processes. Activation of the Calpain family has been related to vessel wall degradation in animal models, and correlated with histological alterations in the dilated aorta in Marfan patients. The aim of our study[for full text, please go to the a.m. URL], 130. Kongress der Deutschen Gesellschaft für Chirurgie

Introduction: Flavonoids are antioxidant agents currently employed in the treatment of different entities, like cancer or atherosclerosis, to reduce inflammation. Endothelial protective effects of flavonoids have been postulated. We investigated the influence of Venoruton®, hydroxyethyl rutoside,[for full text, please go to the a.m. URL], 130. Kongress der Deutschen Gesellschaft für Chirurgie

Despite considerable current progress, cardiovascular diseases (CVD) represent the number one case of death world-wide. Although stem cell therapy has proved its substantial therapeutic potential improving angiogenesis, the underlying mechanisms are still under investigation. The first part of this study was entertained to analyze the multiple steps involved in angiogenesis, focusing on pivotal established factors such as CXCL1 and CXCL12 and VEGF, and laying a particular focus on the emerging role of the angiogenic capacity of the cytokine/chemokine MIF, under normoxic as well as under the hypoxic conditions. In the second part, MIF’s pro-angiogenic potential and its functional receptor CXCR2 were investigated with regard to their role in improving neo-angiogenesis or in conveying protection after myocardial I/R injury. Isolated mouse EPCs and murine embryonic EPCs (eEPCs) were analyzed for the expression and secretion of known angiogenic factors and chemokines as well as the components of the MIF/CXC chemokine receptor axis. In particular, the influence of hypoxic versus normoxic stimulation was assessed. Hypoxic stimulation induced an up-regulation of the surface expression of CXCR2 and CXCR4 but not CD74 on (e)EPCs and potently triggered the secretion of CXCL12, CXCL1, MIF, and vascular endothelial growth factor (VEGF). These EPC-derived factors potently stimulated the chemotactic and transmigration activity as well as adhesive capacity of EPCs, with MIF and VEGF exhibiting the most potent effects under hypoxic conditions. MIF-, VEGF-, CXCL12-, and CXCL1-stimulated EPCs markedly enhanced tube formation in vitro, with again MIF and VEGF exhibiting the strongest effect following hypoxic treatment. Tube formation as assessed by an in vivo implantation model utilizing angiogenic factor-loaded matrigel plugs was only promoted by VEGF. Co-loading of plugs with eEPCs and angiogenic proteins led to enhanced tube formation by CXCL12 but not the other factors, whereas MIF was the only angiogenic factor able to induce a differentiation towards an endothelial and SMCs phenotype, the latter indicating collateralization capacity. Surprisingly, CXCL12, which is a main chemoattractant for smooth muscle progenitor cells, inhibited SMC differentiation. As shown in the first part of my thesis, MIF plays also a crucial role in EPC-derived angiogenesis. Thus, the effect of endogenous MIF on neo-angiogenesis in vivo via CXCR2 was investigated. For this purpose, myocardial I/R was induced in irradiated wild-type mice reconstituted with wildtype (wt) or Cxcr2-/- BM and Cxcr2-/- mice reconstituted with wt BM. The mice were treated with anti-MIF antibody or isotype control and heart functions, infarct size as well as the inflammatory response were analyzed. In conclusion, it can be stated that MIF and its functional receptor CXCR2 together are crucial players in myocardial regeneration and neo-angiogenesis. This study gives new insight on how MIF can positively amplify neo-angiogenesis by regulating pro-inflammatory cell recruitment from the circulation after I/R injury and inducing capillary formation. Angiogenesis is a multi-step process, involving a complex interplay between the endothelium, pro-angiogenic factors and recruited EPCs. Here, I have identified a pivotal role for EPC-derived pro-angiogenic MIF, VEGF and MIF receptors in EPC recruitment following hypoxic challenge, EPC differentiation and subsequent tube and vessel formation, whereas CXCL12, a mediator of early EPC recruitment, does not contribute to the remodeling process. These findings have important implications for the devising of pro-angiogenic therapies in the treatment of CVD and point out the need to precisely identify the molecular players and sequence of steps in new vessel formation.