Abstract 18382: Novel role of Protein Tyrosine Phosphatase 1B in Regulating ROS Production in Macrophages Required for Reparative Angiogenesis Induced by Hindlimb Ischemia
Neovascularization is important repair process that is dependent on inflammation and angiogenesis. We demonstrated that: NADPH oxidase-derived reactive oxygen species (ROS) produced from inflammatory cells and endothelial cells (ECs) play a role in post-ischemic neovascularization; and that PTP1B negatively regulates VEGF signaling involved in angiogenesis in cultured endothelial cells (ECs). PTP1B is also expressed in inflammatory cells and implicated in type2 diabetes and obesity; however, its physiological role in post-ischemic neovascularization in vivo remains unknown. Here we show that PTP1B expression is markedly increased in mice hindlimb ischemia. PTP1B knockout (KO) mice exhibit enhanced capillary density in ischemic, non-inflammatory in upper limb (22%) at day 7, which is consistent with role of PTP1B as negative regulator for angiogenesis. However, mice lacking PTP1B show reduced blood flow recovery (52 %), capillary density (36%) and α-actin positive arterioles (51%) in lower limb with severe damage. Bone marrow (BM) transplantation reveals that PTP1B in BM-derived inflammatory cells in part contributes to full recovery of blood flow. We thus investigated role of PTP1B in inflammatory cells and found that Mac-3+ macrophage infiltration is rather enhanced while ROS production (46%) is markedly reduced in ischemic tissue of PTP1B KO mice. Mechanistically, mRNA of Nox2, but not Nox1 or Nox4, is markedly decreased (67%) in PTP1B KO ischemic tissues. Consistent with this, thioglycollate-induced peritoneal macrophage recruitment is also enhanced (2.2-fold), but ROS level is decreased (44%) in PTP1B KO macrophages. These suggest that infiltrated PTP1B KO macrophages may not have angiogenic function due to loss of ROS. Indeed, ischemia-induced induction of VEGF, which is mainly produced by infiltrated macrophages is inhibited in PTP1B KO mice. In summary, PTP1B functions as negative regulator for EC-dependent and inflammation-independent angiogenesis but also positive regulator for ROS production in macrophages, which is required for induction of angiogenic growth factors in ischemic tissues. The balance of PTP1B-induced effects on both cell types may contribute to the effective reparative post-ischemic neovascularization.
- © 2010 by American Heart Association, Inc.