INDIVIDUAL RESEARCHERKevin Pumiglia , Ph.D.
Education1993 - Ph.D. from University of Connecticut Health Center
Endothelial cells proliferate, migrate and ultimately differentiate to form tubular capillaries. This process, known as angiogenesis, is critical for providing oxygen and nutrients to developing tissues in the embryo, and for growth and repair processes in the adult. The growth and metastasis of tumors is largely dependent upon the tumor's ability to stimulate angiogenesis. One of the mechanisms by which tumors promote the growth of their own blood supply is by increasing production of soluble angiogenic growth factors. One of the most potent of these factors is called Vascular Endothelial Growth Factor or VEGF. This factor is secreted by cells undergoing hypoxic stress, by many neoplastic cells, and by normal cells of the body, when they are stimulated to proliferate. When VEGF binds to its cognate receptors, localized on endothelial cells, it induces a variety of cellular changes. These include stimulated mitogenesis, increased vascular permeability, and changes in the expression of multiple extracellular matrix remodeling genes. Ultimately, this results in the formation of new capillary structures. The goals of our laboratory are to unravel the molecular signals used by VEGF to stimulate endothelial cell growth and differentiation. Using this information we would ultimately like to manipulate the ability of tumors to stimulate angiogenesis (and thereby inhibit tumor growth and spread) using gene transfer techniques. This information should be equally efficacious for use in the manipulation of the angiogenic response in cardiovascular disease states, so called "therapeutic angiogenesis". Our approach is to genetically manipulate individual signaling pathways suspected of being involved in the various VEGF responses. Genetically modified endothelial cells are studied using a number of molecular, physiologic, and biochemical assays in vitro. The relevance of these pathways to tumor angiogenesis is also studied in vivo using a variety of tumor models as well as transgenic mice. Initial efforts in the lab are directed at understanding the role of the small GTP-binding protein Ras, and its downstream pathways, in the stimulation of angiogenesis by VEGF. More recently we have become interested in the mechanisms by which environmental information from the extracellular environment is coordinated by the endothelial cell and modulates the VEGF response. For more information please see our web site at www.pumiglialab.com
- Meadows KN, Bryant P, and Pumiglia K. (2001) Vascular endothelial growth factor induction of the angiogenic phenotype requires Ras activation. J Biol Chem 276:49289-49298.
- Venkiteswaran K, Xiao K, Summers S, Calkins CC, Vincent PA, Pumiglia K, and Kowalczyk AP. (2002) Regulation of endothelial barrier function and growth by VE-cadherin and the Armadillo family proteins plakoglobin and ß-cateinin. Am J Physiol Cell Biol 283:C811-C821.
- Meadows K, Bryant P, Vincent PA, and Pumiglia K. (2004) Activated Ras is sufficient to induce an angiogenic phenotype in primary endothelial cells. Oncogene 23:192-2004.
- McMullen M, Keller R, Sussman M, Pumiglia K. (2004) Vascular endothelial growth factor-mediated activation of p38 is dependent upon Src and RAFTK/Pyk2. Oncogene (in press).