Microgravity and space radiation exert either opposite or synergic effects on single molecular pathways

Microgravity and space radiation (SR) are two highly influential factors affecting humans in space flight. Many health problems reported by astronauts derive from endothelial dysfunction and impaired homeostasis. Here we describe the adaptive response of human, capillary endothelial cells to space. Reference samples on ground and at 1g onboard allowed discrimination between the contribution of microgravity and SR within the combined response to space. Cell softening and reduced motility occurred in space, with loss of actin stress fibers and a greater distribution of microtubules and intermediate filaments in compensation. The frequency of primary cilia also increased. DNA repair mechanisms were indeed activated. Transcriptomics highlighted the opposing effect of microgravity from SR on specific molecular pathways: radiation, unlike microgravity, stimulated pathways for endothelial activation (hypoxia, inflammation), DNA repair and apoptosis, promoting an ageing-like phenotype; microgravity, unlike SR, activated pathways for metabolism and pro-proliferation phenotype. Thus, microgravity and SR should be considered separately to tailor effective countermeasures to protect astronauts’ health. To identify transcriptional changes induced by microgravity, space radiation, and their combination together with other stimuli in space flight, we used a model of human endothelial cells of microvascular origin (HMEC-1). Space samples were exposed to environmental microgravity (g) or set inside the centrifuge reproducing 1g; on ground samples were used as ground control.