Biomechanics and mechanomedicine in the vascular system

Abstract

The vascular system is the most important tissue to supply nutrients and blood to the whole body, which is tightly linked to the life activities, e.g., immunity, tissue repair, etc. The homeostasis of vascular structure and function, especially the endothelial cells (ECs), plays an important role in maintaining the physiological functions of the body. Many factors affect the homeostasis of the vascular system, e.g., microenvironment, microstructure, and microregulation. Mechanical properties of cells have been found closely interacting with physiological/pathological conditions, while so far, few studies have been done to investigate the possible influence of cell mechanics on vascular functions. This thesis explores the important role of biomechanics in vascular homeostasis by investigating the following three factors of the microenvironment, microstructure and microregulation. Firstly, the impact of changes in the microenvironment of hyperglycemia caused by diabetes on the mechanics of ECs and damage of the homeostasis of the vascular system are explored. The stiffness of ECs has significantly dependence on the glucose concentration, which leads to significant alteration of cell migration and proliferation. The rearrangement of the cytoskeleton induced by hyperglycemia through Cdc42 attribute to the alteration of the stiffness of the ECs and their dysfunctions. Therefore, it is expected that Cdc42 may be a possible therapeutic target for the various clinical vascular complications of diabetes. Secondly, the relationship between microstructure and vascular system homeostasis was investigated by selecting leukostasis caused by leukemia . We find that K562 cells treated by PMA show nearly a threefold increase in elastic modulus and worst motility. Besides, the cytoskeleton protein a-tubulin and vimentin have a significant increase after PMA treatment which may be a reason for the elastic modulus increase. Thus, the results indicate that PMA has a significant influence on the stiffness and motility of the K562, leukostasis, and vascular damage. Thirdly, inflammatory factors, as one of microregulators, severely damage the homeostasis of the vascular system. In the repair process of osteoarthritis (OA), the stability of the vascular system of the subchondral bone is vital to the entire process. Here, a drug delivery system, magnesium-based metal-organic framework (Mg-MOF-74), is designed to load ketoprofen to achieve the goal of angiogenesis, osteogenesis, and anti-inflammation for treating OA. The results indicate that the prepared Mg-MOF-74 structure is stable and high loading capacity of ketoprofen (>20% w/w). Furthermore, in vitro cell experiments illustrate that the new drug system has no cytotoxicity, up-regulates the osteogenic cytokines, down-regulates the inflammatory factors in MG63 cells, and up-regulates angiogenesis-related factors in HUVECs. Therefore, Mg-MOF-74 can be a drug carrier and a medicine to treat OA contributing to released Mg2+, which favors promoting osteogenesis and angiogenesis and regulating inflammation. By studying the above three cases, this thesis elaborates on the relationship between biomechanics and vascular homeostasis from the perspectives of the microenvironment, microstructure, and microregulation. Biomechanics, especially deformability, is found to be very important for maintaining the function of vascular. Therefore, in the future, mechanical factors are an important factor that must be considered when studying vascular-related diseases.