The endothelial cells (ECs), which line the inner surface of vessels, play a fundamental role in maintaining vascular integrity and tissue homeostasis, since they regulate local blood flow and other physiological processes. ECs are highly sensitive to mechanical stress, including hypergravity and microgravity. Indeed, they undergo morphological and functional changes in response to alterations of gravity. In particular microgravity leads to changes in the production and expression of vasoactive and inflammatory mediators and adhesion molecules, which mainly result from changes in the remodelling of the cytoskeleton and the distribution of caveolae. These molecular modifications finely control cell survival, proliferation, apoptosis, migration, and angiogenesis. This review summarizes the state of the art on how microgravity and hypergravity affect cultured ECs functions and discusses some controversial issues reported in the literature.

Aldehyde dehydrogenase 1A1 (ALDH1A1), a member of aldehyde dehydrogenase family, is a marker of stemness in breast cancer. During tumor progression cancer stem cells (CSCs) have been reported to secrete angiogenic factors to orchestrate the formation of pathological angiogenesis. This vasculature can represent the source of self-renewal of CSCs and the route for further tumor spreading. The aim of the present study has been to assess whether ALDH1A1 controls the output of angiogenic factors in breast cancer cells and regulates tumor angiogenesis in a panel of in vitro and in vivo models. Stemness status of breast cancer cells was evaluated by the ability to form turmorspheres in vitro. A transwell system was used to assess the angiogenic features of human umbilical vein endothelial cells (HUVEC) when co-cultured with breast cancer cells MCF-7 harboring different levels of ALDH1A1. Under these conditions, we survey endothelial proliferation, migration, tube formation and permeability. Moreover, in vivo, MCF-7 xenografts in immunodeficient mice allow to evaluate blood flow, expression of angiogenic factors and microvascular density (MVD). In MCF-7 we observed that ALDH1A1 activity conferred stemness property and its expression correlated with an activation of angiogenic factors. In particular we observed a significant upregulation of hypoxia inducible factor-1α (HIF-1α) and proangiogenic factors, such as vascular endothelial growth factor (VEGF). High levels of ALDH1A1, through the retinoic acid pathway, were significantly associated with VEGF-mediated angiogenesis in vitro. Co-culture of HUVEC with ALDH1A1 expressing tumor cells promoted endothelial proliferation, migration, tube formation and permeability. Conversely, downregulation of ALDH1A1 in MCF-7 resulted in reduction of proangiogenic factor release/expression and impaired HUVEC angiogenic functions. In vivo, when subcutaneously implanted in immunodeficient mice, ALDH1A1 overexpressing breast tumor cells displayed a higher expression of VEGF and MVD. In breast tumors, ALDH1A1 expression primes a permissive microenvironment by promoting tumor angiogenesis via retinoic acid dependent mechanism. In conclusion, ALDH1A1 might be associated to progression and diffusion of breast cancer.

Microgravity-induced bone loss is currently a significant and unresolved health risk for space travelers, as it raises the likelihood for irreversible changes that weaken skeletal integrity and the incremental onset of fracture injuries and renal stone formation. Another issue related to bone tissue homeostasis in microgravity is its capacity to regenerate following fractures due to weakening of the tissue and accidental events during the accomplishment of particularly dangerous tasks. Today, several pharmacological and non-pharmacological countermeasures to this problem have been proposed, including physical exercise, diet supplements and administration of antiresorptive or anabolic drugs. However, each class of pharmacological agents presents several limitations as their prolonged and repeated employment is not exempt from the onset of serious side effects, which limit their use within a well-defined range of time. In this review, we will focus on the various countermeasures currently in place or proposed to address bone loss in conditions of microgravity, analyzing in detail the advantages and disadvantages of each option from a pharmacological point of view. Finally, we take stock of the situation in the currently available literature concerning bone loss and fracture healing processes. We try to understand which are the critical points and challenges that need to be addressed to reach innovative and targeted therapies to be used both in space missions and on Earth.

Cardiovascular functionality strictly depends on endothelial cell trophism and proper biochemical function. Any condition (environmental, pharmacological/toxicological, physical, or neuro-humoral) that changes the vascular endothelium has great consequences for the organism’s wellness and on the outcome and evolution of severe cardiovascular pathologies. Thus, knowledge of the mechanisms, both endogenous and external, that affect endothelial dysfunction is pivotal to preventing and treating these disorders. In recent decades, significant attention has been focused on gut microbiota and how these symbiotic microorganisms can influence host health and disease development. Indeed, dysbiosis has been reported to be at the base of a range of different pathologies, including pathologies of the cardiovascular system. The study of the mechanism underlying this relationship has led to the identification of a series of metabolites (released by gut bacteria) that exert different effects on all the components of the vascular system, and in particular on endothelial cells. The imbalance of factors promoting or blunting endothelial cell viability and function and angiogenesis seems to be a potential target for the development of new therapeutic interventions. This review highlights the circulating factors identified to date, either directly produced by gut microbes or resulting from the metabolism of diet derivatives as polyphenols.

Wound healing is a complex phenomenon that involves different cell types with various functions, i.e., keratinocytes, fibroblasts, and endothelial cells, all influenced by the action of soluble mediators and rearrangement of the extracellular matrix (ECM). Physiological angiogenesis occurs in the granulation tissue during wound healing to allow oxygen and nutrient supply and waste product removal. Angiogenesis output comes from a balance between pro- and antiangiogenic factors, which is finely regulated in a spatial and time-dependent manner, in order to avoid insufficient or excessive nonreparative neovascularization. The understanding of the factors and mechanisms that control angiogenesis and their change following unloading conditions (in a real or simulated space environment) will allow to optimize the tissue response in case of traumatic injury or medical intervention. The potential countermeasures under development to optimize the reparative angiogenesis that contributes to tissue healing on Earth will be discussed in relation to their exploitability in space.