Harris J. Granger, PhD
Education and Post-Graduate Training
BS, Microbiology, 1966, University of Southwestern Louisiana
PhD, Physiology, 1970, University of Mississippi Medical Center
My research focuses on cell signaling mechanisms and the physiology of postcapillary venules. Postcapillary venules are the primary sites of angiogenesis, inflammation, and the extravasation of fluid, proteins, leukocytes and tumor cells. The wall of these microvessels consists of a continuous, internal layer of endothelium and a discontinuous, external layer of pericytes.
The ability of hypoxia to stimulate the growth of new vessels in the heart is an integrating theme of the angiogenesis research program. We have investigated the roles of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) in modulating EC secretion, migration, proliferation, tube formation, and differentiation. Currently, we are studying temporal patterns of genomic and proteomic (especially kinases) responses to VEGF activation of endothelial cells using high-throughput microarray technology and bioinformatics tools.
Our studies of venular permeability focus on the role of nitric oxide and the p42/44 MAP kinase cascade as common cytosolic signal pathways in hyperpermeability states. The signaling mechanisms responsible for hyperpermeability associated with inflammation and certain growth factors (e.g. VEGF) have been investigated. In addition, the interaction of cytoskeletal activation and EC adhesion (integrins, focal adhesion kinase) to the basement membrane and neighboring cells (cadherins) provides an integrating paradigm for analysis of the changes in cell shape and transport pathways.
To obtain deeper insights into the function of microvessels, we are developing a mathematical model of EC functions. The model includes the behavior of ion channels, membrane transporters, calcium-binding proteins, and numerous signaling pathways. Computer simulations provide detailed information about cellular behavior under a wide variety of stresses.
- Yuan Y, Granger HJ, Zawieja DC, DeFily DV, Chilian WM. Histamine increases venular permeability via a phospholipase C-NO synthase-guanylate cyclase cascade. Am J Physiol 264:H1734-H1739, 1993.
- Wu HM, Huang Q, Yuan Y, Granger HJ. VEGF induces NO-dependent hyperpermeability in coronary venules. Am J Physiol 271:H2735-H2739, 1996.
- Hood J, Granger HJ: Protein kinase G mediates vascular endothelial growth factor induced raf-1 activation and proliferation in human endothelial cells. J Biol Chem 273: 23504-23508, 1998.
- Hood JD, Meininger CJ, Ziche M, Granger HJ. VEGF upregulates ecNOS message, protein, and NO production in human endothelial cells. Am J Physiol 274: H1054-H1058, 1998.
- Wu HM, Yuan Y, Zawieja DC, Tinsley J, Granger HJ: Role of phospholipase C, protein kinase and calcium in VEGF-induced venular hyperpermeability. Am J Physiol 276: H535-542, 1999.
- Wu MH, Ustinova E, Granger HJ. Integrin binding to fibronectin and vitronectin maintains the barrier function of isolated porcine coronary venules. J Physiol 532: 785-91, 2001.
- Steinle JJ, Meininger CJ, Forough R, Wu G, Wu MH, Granger HJ. Eph B4 receptor signaling mediates endothelial cell migration and proliferation via the phosphatidylinositol 3-kinase pathway. J Biol Chem 277: 43830-5, 2002.
- Steinle JJ, Booz GW, Meininger CJ, Day JN, Granger HJ. Beta 3-adrenergic receptors regulate retinal endothelial cell migration and proliferation. J Biol Chem 278: 20681-6, 2003.
- Wu MH, Yuan SY, Granger HJ. The protein kinases MEK1/2 mediate vascular endothelial growth factor- and histamine-induced hyperpermeability in porcine coronary venules. J Physiol 563:95-104, 2005.
- Dawson NS, Zawieja DC, Wu MH, Granger HJ. Signaling pathways mediating VEGF165-induced calcium transients and membrane depolarization in human endothelial cells. FASEB J 20:991-3, 2006.