Research
Publications

How the seemingly diverse signals driving vascular remodeling and angiogenesis are integrated into a final common pathway is a key question in biology. Vascular remodeling is fundamental to many diseases, including cancer, arthritis, atherosclerosis, restenosis after angioplasty, and both systemic and pulmonary hypertension. Research in Dr. Olson's laboratory focuses on molecular mechanisms regulating pathogenic vascular remodeling and angiogenesis.

Vascular remodeling is a progressive multi-stage and multi-factorial process caused by inappropriate cellular growth and differentiation, and accumulation of extracellular matrix proteins such as fibronectin in each layer of the arterial wall. We have shown elevated vascular contents of thepolyamines (putrescine, spermidine and spermine) are essential for development of monocrotaline (MCT)- and hypoxia-induced pulmonary vascular remodeling and the ensuing hypertension in rats. Polyamines are essential for the development of restenosis after angioplasty and systemic hypertension. Our research addresses the working hypothesis that a central convergence point for the multiple signaling pathways driving vascular remodeling and angiogenesis is
ornithine decarboxylase (ODC), the first enzyme in polyamine biosynthesis.

Although many signaling cascades are initiated by cytokines, growth factors and redox-active molecules in response to the injury and inflammation associated with vascular diseases, the vascular remodeling
response is likely due to the combinatorial interactions of intracellular signaling pathways and transcription factors. Our research addresses how specific growth and transcription factors (such as c-myc, NFkB, CREB), specific fibronectin isoforms, cell cytoskeletal structures and polyamines modulate vascular pathogenesis. Studies include mechanisms regulating ODC and fibronectin transcription, and vascular responses produced by the transfer of exogenous functional ODC or fibronectin genes. A comprehensive approach is used employing animals, isolated tissues and cultured cells, and biochemical and molecular biological methodologies such as gene transfer/therapy. New pharmacologic therapies for pulmonary and cardiovascular diseases ultimately will evolve from these research results.

1. Olson JW, U Orlinska & MN Gillespie. Polyamine synthesis blockade reverses monocrotaline- induced pneumotoxicity in rats. Biochem Pharmacol 38:2903-2910, 1989.

2. Shiao R-T, JW Olson, HB Kostenbauder & MN Gillespie. Mechanism of lung polyamine accumulation in chronic hypoxia pulmonary hypertension. Amer J. Physiol 259 (3):L351-58, 1990.

3. Lipke DW, SS Arcot, MN Gillespie & JW Olson. Temporal alterations in specific basement membrane components in lungs from monocrotaline-treated rats. Am. J Respir Cell Mol Biol 9:418-428, 1993.

4. Arcot SS, JA Fagerland, DW Lipke, MN Gillespie & JW Olson. Basic fibroblast growth factor alterations during development of monocrotaline-induced pulmonary hypertension in rats. Growth Factors 12:121-130, 1995.

5. Aziz SM, MP Gosland, PA Crooks, JW Olson & MN Gillespie. A novel polymeric spermine conjugate inhibits polyamine transport in pulmonary artery smooth muscle cells. J Pharmacol Exp Ther 274:181-186, 1995.

6. Harrod, KS, JW Olson & MN Gillespie. Regulation of ornithine decarboxylase by hypoxia in pulmonary artery smooth muscle cells. Amer J Physiol 271:L31-L37, 1996.

7. Graff, JR, A DeBenedetti, JW Olson, P Tamex, RA Casero Jr and SG Zimmer. Translation of ODC mRNA and polyamine transport are suppressed in ras-transformed CREF cells by depleting translation initiation factor 4E. Biochem Biophys Res Commun 240:15-20, 1997.

8. P. Babal, S.M. Manuel, J.W. Olson, and M.N. Gillespie. Regulation of Polyamine Uptake by Hypoxia in Rat Lungs and Pulmonary Arteries. Interactions Between Endothelial and Smooth Muscle Cells. Amer. J. Physiol: Lung Cell Molec. Physiol. 278:L610-L617 (2000).

9. P. Babal, M. Ruchko, J.W. Olson, and M.N. Gillespie. Interactions Between Agmatine and Polyamine Uptake Pathways in Rat Pulmonary Artery Endothelial Cells. Gen. Pharmacol. 34:255-261 (2000).

10. P. Babal, M. Ruchko, C.C. Campbell, S.P. Gilmour, J.L. Mitchell, J.W. Olson, and M.N. Gillespie. Regulation of Ornithine Decarboxylase Activity and Polyamine Transport by Agmatine in Rat Pulmonary Artery Endothelial Cells. J. Pharmacol. Exp. Ther. 296:372-377 (2001).

11. R. Chen, K.S. Harrod, J.W. Olson, and M.N. Gillespie. Regulation of Gadd153 mRNA Expression by Hypoxia in Pulmonary Artery Smooth Muscle Cells. Res. Com. Chem. Path. Pharmacol. 108:3-14 (2000).

12. P. Babal, M. Ruchko, K. Ault-Ziel, L. Cronenberg, J.W. Olson, and M.N. Gillespie. Regulation of Ornithine Decarboxylase Activity and Polyamine Import by Hypoxia in Pulmonary Artery Endothelial Cells. Amer. J. Physiol: Lung Cell Molec. Physiol. 282:L840-L846 (2002).