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.
