Abstract
To conserve energy in times of limited resource availability, particularly during cold winters, hibernators suppress even the most basic of physiologic processes. Breathing rates decrease from 40 breaths/minute to less than 1 breath/min as they decrease body temperature from 37 °C to ambient. Nevertheless, after months of hibernation, these incredible mammals emerge from torpor unscathed. This study was conducted to better understand the protective and possibly anti-inflammatory adaptations that hibernator lungs may use to prevent damage associated with entering and emerging from natural torpor. We postulated that the differential protein expression of soluble protein receptors (decoy receptors that sequester soluble ligands to inhibit signal transduction) would help identify inhibited inflammatory signaling pathways in metabolically suppressed lungs. Instead, the only two soluble receptors that responded to torpor were sVEGFR1 and sVEGFR2, two receptors whose full-length forms are bound by VEGF-A to regulate endothelial cell function and angiogenesis. Decreased sVEGFR1/2 correlated with increased total VEGFR2 protein levels. Maintained or increased levels of key γ-secretase subunits suggested that decreased sVEGFR1/2 protein levels were not due to decreased levels of intramembrane cleavage complex subunits. VEGF-A protein levels did not change, suggesting that hibernators may regulate VEGFR1/2 signaling at the level of the receptor instead of increasing relative ligand abundance. A panel of angiogenic factors used to identify biomarkers of angiogenesis showed a decrease in FGF-1 and an increase in BMP-9. Torpid lungs may use VEGF and BMP-9 signaling to balance angiogenesis and vascular stability, possibly through the activation of SMAD signaling for adaptive tissue remodeling.
Highlights
In response to colder days and limited food abundance, some homeothermic endotherms use adaptive heterothermy and metabolic rate depression to save precious energy stores
Presenilin 2 can be proteolytically cleaved into an active form that can be detected at 23 kDa, where a strong band was present for ground squirrel
The γ-secretase complex can cleave over 60 intramembrane substrates (De Strooper, 2005; De Strooper, Iwatsubo & Wolfe, 2012), so further analysis will be warranted to characterize its complete regulatory role during hibernation. These results suggest that the VEGFR1 and VEGFR2 signaling pathways are less inhibited by decoy receptors and that VEGFR2 may be upregulated to augment VEGF signaling during torpor
Summary
In response to colder days and limited food abundance, some homeothermic endotherms use adaptive heterothermy (lowering body temperature from 37 C to ambient 0–5 C) and metabolic rate depression to save precious energy stores. Angiogenic signaling in the lungs of a metabolically suppressed hibernating mammal (Ictidomys tridecemlineatus). Hibernators ensure proper tissue oxygenation by increasing cardiac contractile strength to pump viscous blood and decreasing the levels of circulating clotting factors and white blood cells to minimize blood clotting (Wang & Wolowyk, 1988; Bouma et al, 2013; Sahdo et al, 2013; Cooper et al, 2016). Despite significant decreases in overall oxygen intake and body temperature, as well as possible oxidative insult from apnoic breathing, tissue damage has never been reported for hibernator lung
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