Studying macro- and microvascular responses to major surgery to develop preventive strategies for perioperative complications

Complications occur in up to 70% of patients undergoing surgery and may lead to further morbidity or even mortality. Systemic and local inflammatory processes in small and large blood vessels can cause such complications and therapeutic strategies are required for their prevention or treatment. In this thesis, we focused on understanding and targeting processes that cause inflammation after surgery in large and small blood vessels. We showed that a sharp drop in high-density lipoprotein cholesterol was strongly associated with the occurrence of heart attacks in patients undergoing vascular surgery. Further, we demonstrated smaller plaques in a model of atherosclerosis-prone mice that were lacking the protein Regulator of G Protein Signalling 5, which modulates processes for signal transduction within cells. To elucidate the inflammatory processes in small blood vessels, we generated a model to expose endothelial cells to patient plasma, obtained before and after surgery, under altered blood flow conditions. Furthermore, we identified the protein tyrosine kinases Axl and Fyn as therapeutic targets in microvascular endothelial inflammation induced by the acutely elevated pro-inflammatory mediator Tumour Necrosis Factor . Overall, our aim was to perform studies which can be used to develop strategies to prevent complications after surgery. We used laboratory animal and cell culture models in combination with patient data and materials to improve the current understanding of therapeutic targets for complications after surgery in both large and small blood vessels. While we cannot offer a solution to these problems, we identified multiple possible therapeutic targets that now require further investigations.