Adequate oxygen transport is one of the most important biological processes that maintain cellular integrity. Oxygen transport in a biological system involves both macroscopic (vascular) and microscopic (cellular) pathways. Among several factors affecting the process of oxygen transport, the change in gravitational forces from unit-gravity (unit-g) to microgravity (micro-g) influences metabolic processes, particularly for astronauts, resulting in weight loss and muscle atrophy. However, little data of blood flow in conjunction with oxygen transport are reported for gravitational changes at tissue, vascular, and cellular levels. Therefore, the objective of this dissertation is to investigate the effect of a) viscosity and geometric changes on oxygen transport at vascular levels under unit-g, and b) simulated micro-g on cellular gene expression in oxygen utilization and metabolic processes as compared to unit-g control, using both experimental and numerical approaches.
The effect of blood viscosity and geometric changes on oxygen transport at vascular levels was evaluated. The significant observation is that the lower Hematocrit (Hct) is favorable for increasing the oxygen flux and the minimum oxygen concentration for moderately stenosed arteries under the basal flow condition, while the higher Hct is advantageous downstream from the stenosis for the hyperemic flow.
Subsequently, as an initial step for the tissue- and cellular-level study, numerical analysis of the rotating wall vessels (RWVs) was conducted for optimizing rotating conditions for simulated micro-g. The rotating speed of the vessel needed to increase as the cell/bead diameters became larger, implying the growth of cell aggregates. Based on numerically determined operating conditions of RWVs, oxygen-sensitive rat pheochromocytoma (PC12) cells were cultured in RWVs and prepared for DNA microarray analyses. The microarray results showed that genes involved in the oxidoreductase activity category and several oxidation-sensitive transcription factors were differentially expressed under micro-g as compared to unit-g.
Further, based on the DNA microarray results, nuclear translocation of the nuclear factor kappa B (NF-κB) p65 in a cardiomyocyte cell line (H9c2), which has relevance to the astronauts’ cardiac physiology, was assessed by monitoring the levels of p65 in the nuclear lysates. The results from western blots revealed that the NF-κB p65 protein was differentially expressed under micro-g, which was also confirmed by enzyme-linked immunosorbent assay (ELISA). This transcription-factor result establishes a foundation for further exploration on specific physiological endpoints such as muscle atrophy phenomena.
A comprehensive understanding of the mechanism of oxygen transport and the significant factors that influence oxygen transport such as that which this dissertation presents may further expedite the development of new pharmacological agents for effective treatment of diseases and symptoms related to disturbed oxygen transport.