Eleni Tzima, PhD
Assistant Professor

Education:

BS, University of Leeds, 1996
PhD, University of Leeds, 2000

Mechanisms of vascular endothelial cell signaling and angiogenesis in response to hemodynamic stimuli

Responses of endothelial cells to fluid shear stress

Localized at the interface between the blood and adjacent tissue, endothelial cells are constantly exposed to biomechanical forces derived by the flow of blood. A major focus of activity in the Laboratory is the study of haemodynamic forces, such as wall shear stress, as modulators of vascular endothelial structure and function. Shear stress induces short-term relaxation of arteries, and, on a longer time scale, remodeling of blood vessels. Turbulent shear stress at bifurcations and curves is also a major determinant of atherosclerosis. Shear stress also influences the adhesion of leukocytes to endothelial cells (ECs) as well as the growth of blood vessels and can “promote” metastasis and vascularization of tumors. Hence, the mechanisms of sensing shear stress by ECs are of considerable scientific and medical interest.

Our studies have led to a new model for integrins in shear stress signaling (Fig.1). We find that fluid flow triggers a rapid conformational activation of integrins. These activated integrins subsequently bind to available ECM proteins and initiate signals. These signals include changes in activity of Rho family GTPases which are critical for both cytoskeletal reorganization and changes in gene expression in response to shear stress. Recently, we started unraveling the pathway that leads to integrin activation: a signaling complex at cell-cell junctions comprised of PECAM-1, VE-cadherin and VEGFR2 mediate the activation of PI 3-kinase, which triggers integrin activation in this pathway.

Specially designed in vitro flow devices are used to expose cultured endothelial monolayers to defined flow regimens, and the resultant morphological, biochemical and molecular genetic changes are studied in the context of vascular adaptation, and also the pathogenesis of vascular diseases, in particular atherosclerosis.

Future work will involve elucidation of the shear pathway that leads to integrin activation, working out how signals downstream of integrins mediate endothelial responses to shear, and an analysis of how shear stress influences adhesion and transmigration of leukocytes.

Mechanisms of angiogenesis

Angiogenesis is the biological process by which new blood vessels develop from the preexisting vaculature. A fragment of human TyrRS (mini TyrRS) has potent angiogenic activity. Induction of angiogensis has been proposed as a potential therapeutic strategy to treat myocardial and limb ischemia due to atherosclerotic blockage. Upon occlusion of the main arteries, the development of a collateral circulation is often observed. Collateral vessels appear in relation to a gradually developing high-grade stenosis or occlusion growing at the interface between normal and ischemic tissue. This circulation helps maintain about normal levels of blood supply. This limits damage to the muscle tissue and helps to prevent necrosis. However, if the rate of occlusion exceeds the rate of collateral circulation growth (as is very often the case), then the blood flow level goes below the minimum level required, eventually leading to ischemia or myocardial infarction. Therefore, enhancement of neovascularization by delivery of growth factors to promote angiogenesis may be a useful therapeutic strategy

Angiogenesis is a multi-step process (Fig.2): the angiogenic factor is produced, released, finds its receptor on the endothelial cells, induces signaling, endothelial cell activation, extracellular matrix degradation, endothelial cell proliferation, directional migration, extracellular matrix remodeling, tube and loop formation and vascular stabilization with the establishment of blood flow. We will investigate the effects of mini TyrRS on all these steps of angiogenesis.

Fig.1 Model for signaling in response to flow

Fig. 2 Angiogenesis

Relevant References:

Liu Y, Sweet D, Irani-Tehrani M, Maeda N and Tzima E. Shc coordinates signals from intercellular junctions and integrins to regulate flow-induced inflammation. J. Cell Biol. In press

Goldfinger#, Tzima E#, Stockton, Kiosses, Kinbara, Tkatchenko, Nguyen, Chien and Ginsberg. Localized a4 integrin Phosphorylation Directs Shear Stress-Induced Endothelial Cell Alignment. Circ Res. In review (# equal contribution)

Cheng G, Zhang H, Ewalt K, Yang XL, Tzima E, Schimmel P and Faber JE. Mini-tyrosyl-tRNA Synthetase Regulates Ischemic Angiogenesis, Leukocyte Recruitment and Vascular Permeability. Arterioscl. Thromb. Vasc. Biol. In review

Kapoor M, Zhou Q, Otero F, Myers CA, Bates A, Belani R, Liu J, Luo JK, Tzima E, Zhang DE, Yang XL, Schimmel P. Evidence for annexin II/S100A10 complex and plasmin in mobilization of cytokine activity of human TrpRS. J Biol Chem. 283(4):2070-7.

Greenberg Y, King M, Ewalt K, Yang XL, Schimmel P, Reader JS and Tzima E. The novel fragment of tyrosyl tRNA synthetase, mini-TyrRS, is secreted to induce an angiogenic response in endothelial cells. FASEB J; 2007 Dec 28

Tzima, E. The Role of Small GTPases in Endothelial Cytoskeletal Dynamics and the Shear Stress Response. Circ Res. 2006; 98:176-185.

Tzima, E. and Schimmel P. Tumor angiogenesis inhibition by a natural fragment of a tRNA synthetase. Trends Biochem Sci. 2006 Jan;31(1):7-10.

Tzima E, Irani-Tehrani M, Kiosses WB, Dejana E, Schultz DA, Engelhardt B, Cao G, DeLisser H and Schwartz MA. A mechanosensory complex that mediates the endothelial cell response to fluid shear stress. Nature. 2005;437:426-31.
(Featured at Nature Reviews Drug Discovery 4, 883-883 Research Highlight: “Go with the Flow”; Science STKE, 2005 , p. tw333 Editors' Choice “PECAM-1 as a fluid shear stress sensor”; Faculty of 1000 Biology, Factor 9.8 “Exceptional”)

Tzima E, Reader JS, Irani-Tehrani M, Ewalt KL, Schwartz MA, Schimmel P. VE-cadherin links tRNA synthetase cytokine to anti-angiogenic function. J Biol Chem. 2005;280(4):2405-8.

Katsumi A*, Orr AW*, Tzima E* and Schwartz MA. Integrins in Mechanotransduction. J. Biol. Chem. 2004 279:12001-4.
*These three authors contributed equally and are listed in alphabetical order

Tzima E, Reader JS, Irani-Tehrani M, Ewalt K, Schwartz MA and Schimmel P. Biologically active fragment of a human tRNA synthetase inhibits fluid shear stress-activated responses of endothelial cells. Proc Natl Acad Sci USA, 2003; 100:14903-7.

Tzima E, Kiosses WB, del Pozo MA and Schwartz MA. Localized Cdc42 activation mediates MTOC positioning in endothelial cells in response to fluid shear stress. J. Biol. Chem. 2003; 278: 31020-3.

Tzima E, del Pozo, MA, Kiosses WB, Mohamed S, Li S, Chien S and Schwartz MA. Activation of Rac by shear stress in endothelial cells mediates both cytoskeletal reorganization and effects on gene expression. EMBO J. 2002; 2:6791-800.

Tzima E, del Pozo MA, Shattil SJ, Chien S, Schwartz MA. Activation of integrins in endothelial cells by fluid shear stress mediates Rho-dependent cytoskeletal alignment. EMBO J. 2001;20:4639-47.