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Spaceflight leads to cardiovascular deconditioning in the absence of mitigation strategies. Cardiovascular changes in response to spaceflight are attributed to altered microgravity levels and the ensuing cephalad fluid shift. Overall reductions in physical activity and other factors – such as nutritional changes, elevated CO2 levels, and a demanding workload – also may be contributing factors. Although the literature is mixed, some of the reported cardiovascular changes associated with exposure to the spaceflight environment include reductions in left ventricular mass, transient atrial distension and heart rhythm disturbances. Orthostatic intolerance and stiffer carotid arteries also have been observed in spaceflight crew upon return to Earth. Changes in venous blood flow and thrombus formation also are potential risks of spaceflight.
During deep space explorations, humans will be exposed to even longer periods of microgravity and higher doses of space radiation relative to International Space Station (ISS) missions. The development of effective countermeasures for deep space missions requires an understanding of the anticipated spectrum of cardiovascular outcomes. Human studies as described above have shed light on how the cardiovascular system responds to microgravity (and other current environmental stressors in low Earth orbit). However, there is limited information on whether cardiovascular responses to deep space radiation alone will be similar to the effects of microgravity or in combination. Therefore, in this investigation, we aimed to (1) determine radiation dose and time-dependence on measures of cardiovascular health in crew age-matched female and male mice using simulated space radiation, (2) determine the effects of simulated space radiation singly and in combination with simulated microgravity by hindlimb unloading (HU), and (3) determine whether cardiovascular changes induced by simulated space exposure or in combination with HU correlate with specific and measurable behavioral, neuromotor, and immune outcomes. The sex dependence of the responses to simulated spaceflight factors also was assessed.
Our central hypothesis is that exposure to simulated space radiation results in long-term changes to the transcriptome, redox signaling, and cytokine milieu of cardiovascular tissue, some of which have known links to aging and increased cardiovascular disease (CVD) risk. We hypothesize that exposure to simulated space radiation, in combination with simulated microgravity exacerbates cardiovascular deficits compared to single factor exposure. In our first study, female and male C57BL/6J mice (23-24 week old) were exposed to a single dose of 5, 15, and 50 cGy of 5-ion galactic cosmic radiation (GCR) or sham-treated (0 cGy). Tissues were collected at 14 days and 124 days post-GCR. In a second study, mice underwent one week of simulated microgravity by hindlimb unloading (HU) and then exposed to a single dose of 15 cGy GCR. HU was conducted for an additional two weeks post-GCR exposure. Single factor exposure groups (HU or GCR only) also were included in the study. Tissues were collected after 21 days of HU (14 days post-GCR exposure).
Collectively, our findings show long-term changes in the heart transcriptome after GCR exposure. Some of these genes are linked to the development of cardiovascular disease. A mixture of cardioprotective and CVD-associated transcriptional changes were observed. Proteins levels of a subset of CVD-relevant cytokines show sex differences, but no GCR nor HU effects. In aorta, markers for aging and mitochondrial health showed both sex and age effects. Our findings highlight the importance of sex-specific strategies in monitoring and maintaining cardiovascular health during and after deep space missions.
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