Anoxia Rapidly Induces Changes in Expression of a Large and Diverse Set of Genes in Endothelial Cells

Abstract

Sinusoidal endothelial cells are the predominant vascular surface of the bone marrow and constitute the functional hematopoietic niche where hematopoietic stem and progenitor cells receive cues for self-renewal, survival, and differentiation. In the bone marrow hematopoietic niche, the oxygen tension is usually very low, and this condition affects stem and progenitor cell proliferation and differentiation and other important functions of this region. Here, we have investigated in vitro the response of endothelial cells to a marked decrease in O2 partial pressure to understand how the basal gene expression of some relevant biological factors (i.e., chemokines and interleukins) that are fundamental for the intercellular communication could change in anoxic conditions. Interestingly, mRNA levels of CXCL3, CXCL5, and IL-34 genes are upregulated after anoxia exposure but become downmodulated by sirtuin 6 (SIRT6) overexpression. Indeed, the expression levels of some other genes (such as Leukemia Inhibitory Factor (LIF)) that were not significantly affected by 8 h anoxia exposure become upregulated in the presence of SIRT6. Therefore, SIRT6 mediates also the endothelial cellular response through the modulation of selected genes in an extreme hypoxic condition.

The influence of redox modulation on hypoxic endothelial cell metabolic and proteomic profiles through a small thiol‐based compound tuning glutathione and thioredoxin systems

“…In previous studies conducted by our group with HUVEC maintained in anoxia (<1% O 2 ), transcriptomic analysis revealed that among the dysregulated genes during the O 2 deprivation, particularly Hypoxia‐inducible factor 1α ( HIF ‐ 1α ) and HIF‐1α‐dependent angiogenic factors like the vascular endothelial growth factor (VEGF) emerged 47 . Therefore, RT‐PCR was used to determine the gene expression of HIF ‐ 1α , VEGF , and the Thioredoxins ( TRX ‐ 1 and 2 ), in hypoxic vs normoxic cells (Figure 5).…”

“…In previous studies conducted by our group with HUVEC maintained in anoxia (<1% O 2 ), transcriptomic analysis revealed that among the dysregulated genes during the O 2 deprivation, particularly Hypoxia-inducible factor 1α (HIF-1α) and HIF-1α-dependent angiogenic factors like the vascular endothelial growth factor (VEGF) emerged. 47 Therefore, RT-PCR was used to determine the gene expression of HIF-1α, VEGF, and the Thioredoxins (TRX-1 and 2), in hypoxic vs normoxic cells (Figure 5). The downregulated metabolites are shown in green, the upregulated ones in red, the not detectable ones in gray, and those that do not statistically change (considering normoxia vs. hypoxia and treated group vs. hypoxia) in black.…”

Sirtuin 6 Regulates the Activation of the ATP/Purinergic Axis in Endothelial Cells

“…Thus, understanding the players governing the response of ECs in inflammatory states is crucial to develop aids to maintain endothelial homeostasis and the prevention of vascular diseases. Very recently, we also demonstrated that SIRT6 may prevent oxidative stress damages via the upregulation of NADPH to counteract reactive oxygen species in HUVECs [ 52 ]. Altogether, our results suggest that SIRT6 activation through pharmacological approaches may represent a useful strategy to (a) counteract endothelial inflammatory responses and (b) sustain the production of platelets.…”