Executive Summary : | The human vascular system is influenced by various physiological conditions, including high shear stress, mechanical deformation, and hypoxia, which trigger the release of adenosine triphosphate (ATP) from red blood cells (RBCs) to extracellular space. This ATP-endothelial cell interaction leads to increased vascular permeation, which is responsible for cardiovascular disorders like angioedema. The proposed work aims to develop a flow-based microvasculature-on-a-chip platform to understand the role of mechano-sensitive stimuli in the progression and diagnosis of cardiovascular diseases. Endothelial dysfunction is the most common cause of cardiovascular disorders, and it can occur due to ATP exposure. In vitro studies have reported intracellular alterations and dynamic opening of inter-endothelial junctions in endothelial cells (ECs) when RBCs are absent. However, single- and multi-cell analysis of RBCs in the absence of the endothelium layer, especially under strong mechanical deformation and high shear stress, has revealed ATP release from RBCs. When combined, flow-mediated alterations strongly impact the interaction of RBC-derived ATP with the endothelium, such as through changes in vessel wall permeability, contributing to the development of cardiovascular disorders.
The development of an in vitro "microvasculature on a chip" platform will provide a unique opportunity to explore changes in endothelium functions in 3D and under physiological flow conditions. The proposed microfluidic technique will have significant implications in identifying major elements that compromise endothelial cell function when ATP concentrations are altered, with far-reaching consequences on both cardiovascular and immune system dysfunctions. |