Abstract 13185: Monocyte Specific Hydrogen Sulfide Regulates Arteriogenesis in Murine Hind Limb Ischemia
Background: Monocyte signaling is a dominant and important mediator of arteriogenesis activity and monocyte-signaling responses can be severely impaired during arteriogenesis in various vascular disorders. Hydrogen sulfide (H2S) is produced by cystathionine-γ lyase (CSE), and a potential gasotransmitter that has many positive cardiovascular effects including regulation of monocyte functions. However, molecular mechanisms of monocyte specific H2S regulation of arteriogenesis remain completely unknown.
Hypothesis: Monocyte specific H2S production modulates arteriogenesis during hind limb ischemia via a CSE/H2S/IL-16/bFGF dependent pathway.
Methods: Unilateral hind limb ischemia was induced in WT and CSE-/- mice. Mice were then randomly assigned into 4 groups (8 mice, each group); WT PBS, WT DATS (a hydrogen sulfide donor, 200 μg/kg bid., IV until day 21), CSE-/- PBS, CSE-/- DATS. Monocyte expression and activity of CSE and H2S levels was determined in ischemic conditions both in vitro and in mice. Blood flow was measured using laser Doppler perfusion imaging and the number and diameter of gracillis collaterals were determined using SPY angiography. α-SMA/CD31 and MAC-2/DAPI tissue staining determined mature vessel density and monocyte recruitment. Tissue IL-16, bFGF and VEGF levels were measured by ELISA method.
Results: CSE expression and activity, and H2S levels were increased during ischemia in mouse bone marrow derived and circulating monocytes and tissues. Blood perfusion, blush rate, number and diameter of collaterals and mature vessel density were decreased in CSE-/- mice compared to WT mice, which was rescued by DATS therapy. IL-16 expression and monocyte recruitment but not MCP-1 levels were reduced in CSE-/- mouse ischemic tissue that was restored by DATS treatment. Lastly, bFGF and VEGF levels were significantly less in ischemic tissue of CSE-/- mice that was rescued by DATS therapy.
Conclusions: CSE/H2S regulates arteriogenesis via IL-16 mediated monocyte recruitment and up-regulation of bFGF and VEGF levels in mouse hind limb ischemia of CSE-/- mice. The results of this study may be useful for peripheral arterial disease with defective arteriogenesis.
- © 2013 by American Heart Association, Inc.