Tzima - Research

Endothelial cell signaling in health and disease
 

Cross-section of a carotid artery

My lab is interested in identifying the signaling mechanisms that regulate endothelium function in health and disease. We have two areas of ongoing research:

1.  Mechanotransduction, Blood flow and Cardiovascular Disease

The importance of mechanical force to development, normal physiology and various disease states is well-established. In the cardiovascular system, fluid shear stress, the frictional drag on the endothelium from blood flow, is a major determinant of vascular physiology and pathology. Shear stress acting on the vascular endothelium regulates recruitment/activation of monocytes and structural remodeling of the vascular wall. However, shear stress is also a key factor in atherosclerosis. Atherosclerosis is a chronic inflammatory disease that occurs selectively in areas that experience disturbed flow patterns and shear stress. Our long term goal is to understand how shear stress-dependent inflammatory signaling can be modulated for preventive and therapeutic purposes. The following research avenues are active:

a) The mechanisms by which endothelial cells sense mechanical forces and initiate biochemical signaling pathways. We are collaborating with Rich Superfine’s lab at UNC to apply forces on PECAM-1 and study mechanotransduction.

b) The mechanisms by which endothelial cells respond to “protective” vs. “pathologic” flow. We are investigating the role of PECAM-1 and Shc in these pathways and are particularly interested in biomarkers of disease.

c) The role of shear stress in vivo. Using knockout and transgenic animals, we investigate the role of shear stress in vascular remodeling and heart function.

Endothelial cell immunostained for actin stress fibers (green) and TyrRS (red)

2. 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: 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 have been investigating the molecular mechanism by which miniTyrRS regulates angiogenesis in vitro and in vivo. We found that miniTyrRS increased in vitro proliferation, migration (wound healing), and tube formation of vascular endothelial cells. This project focuses on the ability of miniTyrRS to bind to endothelial cells directly, with the aim of identifying the receptor through which it is acting. Experiments on the possible activity of miniTyrRS on vascular smooth muscle cells are also underway.