S. Joseph Leibovich, Ph.D.
Professor

Office: MSB G677
Lab: MSB G606 / G607
Tel: (973) 972-5404
Fax: (973) 972-7489
Email: leibovic@umdnj.edu

CELL & MOLECULAR BIOLOGY OF WOUND REPAIR AND ANGIOGENESIS

The research interests of my lab. are concerned with the role of macrophages and macrophage-derived factors in controlling the process of neovascularization. Macrophages are exquisitely sensitive to theoir environment, and can be activated either to express inflammatory cytokines, such as TNF a , IL-1 and IL-12, or to express angiogenic growth factors such as VEGF. We have recently discovered a novel pathway that regulates the angiogenic phenotype of macrophages. This pathway involves a synergistic interaction between Toll-like receptor (TLR) agonists (such as endotoxins and non-methylated CpG DNA) and adenosine A 2A receptor agonists, and results in the strong up-regulation of VEGF expression and the strong down-regulation TNF a and Il-12 expression, thus acting as an angiogenic “switch”. This “switch” changes macrophages from an inflammatory to an anti-inflammatory, angiogenic phenotype. The pathway is independent of hypoxia and nitric oxide, and involves signaling through both G-protein coupled receptors and the MyD88 signaling pathway. We are currently studying the signaling pathways involved in this synergistic interaction.

We have found using global gene expression analysis that, in addition to VEGF, a small group of genes is regulated by TLR agonists with adenosine A 2A agonists. Most notably, sphingosine kinase-1 (SK-1), an enzyme that generates the angiogenic lipid sphingosine-1-phosphate from sphingosine, is strongly upregulated in parallel with VEGF. We are currently studying the role of SK-1 in macrophage-dependent angiogenesis.

We have also described a nitric oxide (NO)-dependent pathway in macrophages that regulates the expression of VEGF. We are studying the role of NO in regulating VEGF expression. Analyses using VEGF promoter constructs indicate that NO regulates VEGF gene transcription. However, major regulation of VEGF expression also involves an interaction between NO and pericellular hypoxia, regulating VEGF expression post-transcriptionally. The mechanisms involved in these regulatory pathways are currently under investigation.
 

Representative Publications:

Leibovich, S.J. The Role of Cytokines and Growth Factors in Tumor Angiogenesis. In: Human Cytokines: Their Role in Disease and Therapy:. Eds. Aggarwal, B. and Puri, R. Blackwell Scientific, 1996, pp.539-564.

Leibovich, S.J. , Xiong, M, Elson, E., Sharma, S., Seo, C. and Lanahan, M. The Role of Macrophages in the Control of Angiogenesis in Wound Repair: Nitric Oxide (NO), Angiogenesis Inhibitors and Tumor Suppresser Genes. Exc. Med. Int. Cong. Ser. 1139, Bone Formation and Repair. Eds. Rabie, A.B.R and Urist, M.R. 1997, pp. 101-111. PubMed Citation

Xiong, M., Elson, E. Legarda, D. and Leibovich, S.J. Production of Vascular Endothelial Growth Factor (VEGF) by Murine Macrophages: Regulation by Hypoxia, Lactate and the Inducible Nitric Oxide Synthase Pathway. Am. J. Pathol. 1998, 153, 587-598. PubMed Citation

Leibovich, S.J ., Chen, J.F., Pinhal-Enfield, G., Belem , P.C., Elson, G., Rosania, A., Ramanathan, M., Montesinos, C., Jacobson, M., Schwarzschild, M.A., Fink, J.S., Cronstein, B.  Synergistic up-regulation of vascular endothelial growth factor (VEGF) expression in murine macrophages by adenosine A 2A receptor agonists and endotoxin.  Am. J. Pathol. 160, 2231, 2002. PubMed Citation

Bohl-Masters, K.S., Leibovich, S.J. , Belem , P., West, J.L., Poole-Warren, L.A.   The effects of nitric oxide releasing hydrogel dressings on dermal wound healing in diabetic mice.  Wound Rep. Regen. 10(5), 286-294, 2002. PubMed Citation

Ramanathan, M., Giladi, A., Leibovich, S.J .   Regulation of VEGF gene expression in murine macrophages by nitric oxide and hypoxia.   Exp. Biol. Med.  June 2003,  In press.