Gravitational unloading induces an anti‐angiogenic phenotype in human microvascular endothelial cells

Abstract

Creating conditions similar to those occurring during exposure of cells to microgravity modulates endothelial functions. We have previously demonstrated that human macrovascular endothelial cells in simulated hypogravity proliferate faster than controls, partly because they downregulate interleukin 1alpha. On the contrary, murine microvascular endothelial cells are growth inhibited in simulated hypogravity, and this is due, at least in part, to the decrease of interleukin 6. Since endothelial cells are very heterogeneous and differences between various species have been reported, we exposed human microvascular cells to gravitational unloading and found that it retards cell growth without affecting cell migration. Interestingly, we detected the induction of Tissue Inhibitor of Metalloprotease-2, which inhibits endothelial growth in vitro and angiogenesis in vivo. Together with the finding that hypogravity stimulates the synthesis of nitric oxide, involved also in neovascularization, our results underscore a modulation of the angiogenic properties of microvascular human endothelial cells. We also show that hypogravity inhibits proteasome activity, thus suggesting that post-translational mechanisms are involved in the adaptations of these cells to hypogravity. These results underscore that hypogravity differently impacts on micro- and macro-vascular human endothelial cells. In particular, these results may shed some light on the molecular mechanisms contributing to the impairment of angiogenesis observed in different models in space. Our data might also explain why bioengineered tissues to be used for regenerative medicine fail to neovascularize when assembled in simulated hypogravity.

Culture of human cells in experimental units for spaceflight impacts on their behavior

“…Accordingly, we demonstrated the different response to simulated microgravity of these cells. 14,16 There is one interesting similarity in the behavior of these cells, i.e. the production of ROS dramatically drops when HUVECs and HDMECs are confluent, thus indicating an inverse correlation between cell number and ROS generation.…”

“…Simulated microgravity affects endothelial function and different responses to gravitational unloading have been described in micro-and macrovascular human endothelial cells. [13][14][15][16] We have also shown that microvascular endothelial cells in simulated microgravity release proteins that affect osteoblast behavior in a co-culture system. 17 Recently, both macrovascular 18 and microvascular endothelial cells were flown to the International Space Station (ISS), which offers unique opportunities to study the effect of space on the cells.…”

Growing Tissues in Real and Simulated Microgravity: New Methods for Tissue Engineering

“…Mariotti and Maier reported that only microvascular cells suffer from inhibited growth and angiogenesis, while macrovascular cells proliferated faster when grown on an RWV. 103 Exposing the cells to altered gravity conditions on an RPM led an increased apoptosis rate, 17,53 which was significantly reduced by the addition of vascular endothelial growth factor to the culture medium. 104 Similar effects have also been reported in further studies.…”

Up-regulation of ryanodine receptor expression increases the calcium-induced calcium release and spontaneous calcium signals in cerebral arteries from hindlimb unloaded rats

“…Nevertheless, it is necessary to study the functions activated by spontaneous Ca 2+ oscillations in cerebral arteries, and especially the molecular targets implicated in the proliferation/apoptosis balance, such as transcription factors observed in endothelial cells [25], and also the Ca 2+ sensitivity of myofilaments. Finally, this adaptation appeared to have settled rapidly in 1 week and could persist during 28 days [49,51], yet the time course of the molecular adaptation as well as the effect of a longer exposure to HU and μG remain to be further evaluated.…”