Abstract
Drosophila tracheal terminal branches are plastic and have the capacity to sprout out projections toward oxygen-starved areas, in a process analogous to mammalian angiogenesis. This response involves the upregulation of FGF/Branchless in hypoxic tissues, which binds its receptor Breathless on tracheal cells. Here, we show that extra sprouting depends on the Hypoxia-Inducible Factor (HIF)-alpha homolog Sima and on the HIF-prolyl hydroxylase Fatiga that operates as an oxygen sensor. In mild hypoxia, Sima accumulates in tracheal cells, where it induces breathless, and this induction is sufficient to provoke tracheal extra sprouting. In nontracheal cells, Sima contributes to branchless induction, whereas overexpression of Sima fails to attract terminal branch outgrowth, suggesting that HIF-independent components are also required for full induction of the ligand. We propose that the autonomous response to hypoxia that occurs in tracheal cells enhances tracheal sensitivity to increasing Branchless levels, and that this mechanism is a cardinal step in hypoxia-dependent tracheal sprouting.
Highlights
Animal physiology and development are modulated by a wide variety of external stimuli, such as temperature, light, nutrient availability, and oxygen tension
Drosophila tracheal terminal branches are plastic and have the capacity to sprout out projections toward oxygen-starved areas, in a process analogous to mammalian angiogenesis
This response involves the upregulation of fibroblast growth factor (FGF)/Branchless in hypoxic tissues, which binds its receptor Breathless on tracheal cells
Summary
Animal physiology and development are modulated by a wide variety of external stimuli, such as temperature, light, nutrient availability, and oxygen tension. Angiogenesis is a widespread developmental process that is common to many physiological and pathological conditions such as formation of the placenta, endometrial growth, wound healing, ischemic heart disease, stroke, and cancer (Carmeliet, 2003; Folkman and Klagsbrun, 1987). It encompasses the formation of new capillaries from pre-existing blood vessels, and it is triggered when hypoxic cells secrete angiogenic growth factors, mainly the Vascular Endothelial Growth Factor (VEGF), which binds its receptors on the endothelial cells of blood vessels (Ferrara et al, 2003; Levy et al, 1995; Shweiki et al, 1992). Hydroxylation is mediated by 2-oxoglutarate/iron(II)-dependent prolyl-4-hydroxylases, which use dioxygen as a cosubstrate for catalysis and, are considered to be bona fide oxygen sensors (Bruick and McKnight, 2001; Epstein et al, 2001)
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.
