Thomas N Sager

Publications (2)8.42 Total impact

• Article: Tumor necrosis factor α primes cerebral endothelial cells for erythropoietin-induced angiogenesis.

  Lei Wang, Michael Chopp, Hua Teng, Marianne Bolz, Moniche-Alvarez Francisco, Moniche Ãlvarez Francisco, Danielle Marie Aluigi, Xin Li Wang, Rui Lan Zhang, Søren Chrsitensen, Thomas N Sager, Alexandra Szalad, Zheng Gang Zhang
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  ABSTRACT: Erythropoietin (EPO) enhances angiogenesis in the ischemic brain. Stroke induces secretion of tumor necrosis factor α (TNF-α). We investigated the effect of TNF-α on EPO-induced in vitro angiogenesis in cerebral endothelial cells. Using a capillary-like tubular formation assay, we found that transient incubation of primary rat cerebral microvascular endothelial cells (RECs) with TNF-α substantially upregulated EPO receptor (EPOR) expression and addition of EPO into TNF-α-treated RECs significantly augmented the capillary-like tube formation. Blockage of TNF receptor 1 (TNFR1) suppressed TNF-α-upregulated EPOR expression and abolished EPO-induced tube formation. Attenuation of endogenous EPOR with small interfering RNA (siRNA) also inhibited EPO-enhanced tube formation. Treatment of RECs with EPO activated nuclear factor-kappa B (NF-κB) and Akt. Incubation of the TNF-α-treated endothelial cells with EPO activated vascular endothelial growth factor (VEGF), VEGF receptor 2 (VEGFR2), angiopoietin 1 (Ang1), and Tie2. Blockage of VEGFR2 and Tie2 resulted in reduction of EPO-augmented tube formation. These data indicate that interaction of TNF-α with TNFR1 sensitizes cerebral endothelial cells for EPO-induced angiogenesis by upregulation of EPOR, which amplifies the effect of EPO on activation of the VEGF/VEGFR2 and Ang1/Tie2 pathways. Our results provide the evidence for crosslink between TNF and EPOR to coordinate the onset of angiogenesis in cerebral endothelial cells.
  Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 02/2011; 31(2):640-7. · 5.46 Impact Factor
• Article: Effects of posttraumatic carbamylated erythropoietin therapy on reducing lesion volume and hippocampal cell loss, enhancing angiogenesis and neurogenesis, and improving functional outcome in rats following traumatic brain injury.

  Ye Xiong, Asim Mahmood, Yanlu Zhang, Yuling Meng, Zheng Gang Zhang, Changsheng Qu, Thomas N Sager, Michael Chopp
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  ABSTRACT: Carbamylated erythropoietin (CEPO) is a modified erythropoietin molecule that does not affect hematocrit. In this study, the authors compared the efficacy of a single dose with a triple dose of CEPO treatment for traumatic brain injury (TBI) in rats. Traumatic brain injury was induced by controlled cortical impact over the left parietal cortex. Carbamylated erythropoietin (50 μg/kg) was administered intraperitoneally in rats with TBI at 6 hours (CEPO × 1) or at 6, 24, and 48 hours (CEPO × 3) postinjury. Neurological function was assessed using a modified neurological severity score and foot fault and Morris water maze tests. Animals were killed 35 days after injury, and brain sections were stained for immunohistochemical analysis to assess lesion volume, cell loss, cell proliferation, angiogenesis, and neurogenesis after CEPO treatment. Compared with the vehicle treatment, single treatment of CEPO (6 hours) significantly reduced lesion volume and hippocampal cell loss, enhanced angiogenesis and neurogenesis in the injured cortex and hippocampus, and significantly improved sensorimotor functional recovery and spatial learning in rats after TBI. Importantly, triple dosing of CEPO (6, 24, and 48 hours) further reduced lesion volume and improved functional recovery and neurogenesis compared with the CEPO × 1 group. The authors' results indicate that CEPO has considerable therapeutic potential in TBI and related pathologies and furthermore that repeated dosing in the subacute phase might have important pharmacological relevance.
  Journal of Neurosurgery 11/2010; 114(2):549-59. · 2.96 Impact Factor