Hypoxia and ascorbic acid: two interconnected microenvironmental factors driving collagen biosynthesis

• Ascorbic acid and low oxygen levels (hypoxia) promote collagen biosynthesis • Both factors act on collagen hydroxylases but through different mechanisms • Reciprocal regulation complicates the prediction of the net effect on fibrogenesis • Hypoxia-inducible factors control ascorbic acid intracellular uptake via GLUT1 • Unravelling this complex interplay will help anti-fibrotic therapy design Inadequate collagen deposition is at the core of various pathologies, including non-healing wounds, fibrotic diseases, and tumour progression. It is therefore paramount to fully understand how central effectors affect collagen synthesis and turnover. Here, we will focus on two interconnected physiological effectors, vitamin C (ascorbic acid) and hypoxia (low oxygen levels), which both regulate collagen abundance and organisation. Ascorbic acid (AA) is known to act as a cofactor for collagen-modifying enzymes (collagen prolyl and lysyl hydroxylases) and is vital for collagen thermal stability, proper folding, and fibrillogenesis. Similarly, hypoxia has a strong impact on collagen synthesis, primarily through the stabilisation and activation of the hypoxia-inducible factors (HIFs), which, in turn, upregulate the expression of a range of collagen-modifying enzymes, including the collagen prolyl and lysyl hydroxylases. The consequence of both pathways is an enhanced collagen production, stability, maturation and cross-linking. Since AA and hypoxia both act on collagen hydroxylases, although by different mechanisms, i.e. AA increases the enzymatic activity whereas HIF increases the enzyme production, one can expect a possible synergistic effect of both factors. However, a more complex interplay exists between oxygen levels, AA and collagen as HIF affects AA intracellular uptake via the upregulation of one of its transporters while AA promotes HIF hydroxylation, thus reducing its stability and activity. A comprehensive understanding of this bidirectional control and the feedback loops between hypoxia, AA, and collagen is therefore critical to better tackle pathologies linked to abnormal collagen synthesis.