Endothelial stress by gravitational unloading: effects on cell growth and cytoskeletal organization.

All organisms on Earth have evolved to survive within the pull of gravity. Orbital space flights have clearly demonstrated that the absence or the reduction of gravity profoundly affects eukaryotic organisms, including man. Because (i). endothelial cells are crucial in the maintenance of the functional integrity of the vascular wall, and (ii). cardiovascular deconditioning has been described in astronauts, we evaluated whether microgravity affected endothelial functions. We show that microgravity reversibly stimulated endothelial cell growth. This effect correlated with an overexpression of heat shock protein 70 (hsp70) and a down-regulation of interleukin 1 alpha (IL-1alpha), a potent inhibitor of endothelial cell growth, also implicated in promoting senescence. In addition, gravitationally unloaded endothelial cells rapidly remodelled their cytoskeleton and, after a few days, markedly down-regulated actin through a transcriptional mechanism. We hypothesize that the reduction in the amounts of actin in response to microgravity represents an adaptative mechanism to avoid the accumulation of redundant actin fibers.

Modulation of human endothelial cell behaviour in simulated microgravity.

Eukaryotic organisms are influenced by gravitational forces in their environment. The low gravitational forces endured by organisms in space alter cellular processes in cultured mammalian cells. Endothelial cells represent an interesting model to study because of their crucial role in the pathogenesis of various diseases, from atherosclerosis to inflammation to any situation characterized by dysregulated angiogenesis. We therefore cultured human endothelial cells derived from the umbilical vein in Rotating Wall Vessels (RWV) that simulate microgravity on earth. Under these experimental conditions, cells are viable and no increase in apoptotic rate was observed. They grow reproducibly faster than controls up to 8 days from seeding. Because endothelial proliferation is crucial in angiogenesis, we evaluated other steps required for new blood vessels to form. We found no variations in the levels of metalloproteases and an increased synthesis of their inhibitors (TIMP), suggesting that hypogravity does not induce a pro-angiogenic phenotype. Since i) alterations of blood pressure have been observed in astronauts and ii) endothelial cell synthesize vasoactive molecules, we evaluated the synthesis of nitric oxide and prostacyclin, both potent vasodilators and inhibitors of platelet aggregation. We observed that human endothelial cells grown in hypogavity synthesize higher amounts of prostacyclin and nitric oxide than controls. More studies are ongoing to understand the molecular basis of these events and their role in altering the physiology of the vascular tree.