Changing blood flow in peripheral artery disease

Cardiovascular disease (CVD) is the leading cause of death globally and it is predicted this will remain to increase throughout 2030 to an estimated 23,3 million patients per year. This trend is accompanied by a steep increase in healthcare costs, making it a great health and socio-economic burden. The underlying pathology of CVD is often atherosclerosis, characterized by the development of atherosclerotic plaques in middle- and larger-sized arteries. Peripheral artery disease (PAD) is a disease of the peripheral vasculature, most often in the lower extremities, resulting from significant development of atherosclerotic plaques. Patients suffer from arterial occlusion in different parts of the lower extremities. Around 10 to 20% of the patients suffer from intermittent claudication and up to 2% will suffer from critical limb ischemia with leg amputation as a consequence. Unfortunately, not all patients are eligible for current available treatment options, such as surgical interventions, to restore blood flow and prevent tissue ischemia and tissue loss. There is a great need for new therapeutic options for these patients. A possible option is to stimulate arteriogenesis (collateral artery growth) in patients to recover hampered blood flow in their lower extremities. In order to develop new treatments, there is a need to better understand the process for arteriogenesis. The inflammatory local environment is shown crucial for this process. The research described in this thesis focuses on different inflammatory components involved in arteriogenesis for the development of new therapeutic options. First, we focused on CXCL10, a possible inflammatory target, and its role in cardiovascular disease. Furthermore, we investigated the involvement of CXCL10 in arteriogenesis in a murine hindlimb ischemia model. Next, we focused on the CD200-CD200 receptor inhibitory axis in arteriogenesis using this model, since this axis is described before as critical in infectious diseases. Next, we studied the involvement of small particles, called exosomes, derived from human mesenchymal stem cells and its possible therapeutic effects on arteriogenesis in a murine hindlimb model. In addition, we studied the possible negative effects of a Toll-like receptor 4 inhibitor in arteriogenesis, using the murine hindlimb model. Lastly, we focused on the role of another inflammatory target, leukotriene b4, for its role in two different CVDs, being advanced human atherosclerotic disease and abdominal aortic aneurysm.