Abstract
Every cell in the body requires oxygen for its functioning, in virtually every animal, and a tightly regulated system that balances oxygen supply and demand is therefore fundamental. The vascular network is one of the first systems to sense oxygen, and deprived oxygen (hypoxia) conditions automatically lead to a cascade of cellular signals that serve to circumvent the negative effects of hypoxia, such as angiogenesis associated with inflammation, tumor development, or vascular disorders. This vascular signaling is driven by central transcription factors, namely the hypoxia inducible factors (HIFs), which determine the expression of a growing number of genes in endothelial cells and pericytes. HIF functions are tightly regulated by oxygen sensors known as the HIF-prolyl hydroxylase domain proteins (PHDs), which are enzymes that hydroxylate HIFs for eventual proteasomal degradation. HIFs, as well as PHDs, represent attractive therapeutic targets under various pathological settings, including those involving vascular (dys)function. We focus on the characteristics and mechanisms by which vascular cells respond to hypoxia under a variety of conditions.
Highlights
Maintaining oxygen (O2 ) homeostasis is crucial for the survival of many species and the principal transcription factors that regulate the cellular response to low O2 tension, or hypoxia, are the hypoxia-inducible factors (HIFs)
As prolyl hydroxylase domain (PHD) require oxygen for catalytic action, they are rendered inactive under hypoxic conditions, which allows HIFα stabilization and its translocation into the nucleus, where it interacts with CBP/p300 and HIFβ, and binds to hypoxia responsive elements (HREs) in target genes that typically promote greater transcription
Angiogenesis typically starts in response to the presence of angiogenic cytokines, most noticeably vascular endothelial growth factor (VEGF), and many factors can induce the release of these cytokines, including wounding, ischemia, and hypoxia [62]
Summary
Maintaining oxygen (O2 ) homeostasis is crucial for the survival of many species and the principal transcription factors that regulate the cellular response to low O2 tension, or hypoxia, are the hypoxia-inducible factors (HIFs). As PHDs require oxygen for catalytic action, they are rendered inactive under hypoxic conditions, which allows HIFα stabilization and its translocation into the nucleus, where it interacts with CBP/p300 and HIFβ, and binds to hypoxia responsive elements (HREs) in target genes that typically promote greater transcription. While ECs exposed to chronic hypoxia pivot towards increased glycolysis, biosynthesis of amino acids, carbon metabolism, pentose phosphate pathway, fructose/mannose, and cysteine/methionine metabolism [23], those subjected to acute hypoxia exhibit upregulation of genes involved in pyruvate metabolism and glucose transport, suggesting higher occurrence of glycolysis in hypoxic ECs [24] Besides these direct effects of hypoxia on ECs, many indirect results, such as lactate accumulation in the tumor environment, have been documented, and accruing evidence suggests that glycolytic activity in ECs, along with metabolism in general, might drive angiogenesis [25,26,27]. HPPs, bringing special attention to the intricate regulatory mechanisms of the HPPs and their context-dependent role
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
