Dysregulation of vascular architecture and function is characteristic of a broad spectrum of pathologies, including inflammation, cardiovascular diseases, and cancer. Therefore, the ability to control angiogenesis and vessel remodeling has considerable therapeutic benefit. Blood vessels are lined with a monolayer of tightly joined and mechanically coupled endothelial cells (ECs) that form the barrier between blood and the surrounding tissue. In addition, it is well established that fluid mechanical stresses, such as ones associated with intravascular and transvascular flow, are interpreted by ECs to help form and remodel blood vessels. However, while numerous mechanotransducers in ECs have been proposed, a detailed, quantitative, and complete model of flow sensing by ECs that assists in developing a systematic pathway to controlling angiogenesis does not exist. Thus, there is a significant need for accurately engineered in vitro platforms to systematically study and develop a comprehensive model of the functional outcomes of fluid stresses on blood vessel architecture. Based on our preliminary data and previous discoveries, we hypothesize that intravascular shear stress and transvascular flow impart competing effects in controlling blood vessel remodeling leading to quantifiable changes in angiogenesis vascular permeability, and interendothelial ultrastructure. By thoroughly assessing these parameters, we believe that our approach will identify the biophysical signatures of dysregulated vessel architecture that are characteristic of vascular diseases. Moreover, our goal is to use these biophysical signatures to help design strategies for controlling pathological angiogenesis and vascular permeability. To meet this goal, we will use an integrated strategy in which 3-D microfluidic systems that allow control of physiological levels of pressure and flow conditions and the cell/matrix topology of intact blood vessels will be used in conjunction with high-resolution microscopy and force spectroscopy with nanoscale devices to determine the physical mechanisms by which fluid stresses control angiogenesis and vascular permeability.
In Aim 1, we will quantify changes in blood vessel structure and function in response to fluid stresses.
In Aim 2, we will measure changes in tension at EC junctions in response to fluid stresses.
In Aim 3, we will develop approaches for suppressing angiogenesis and vascular permeability by stabilizing EC junctions. Completion of these studies will help establish a new paradigm for using cellular and subcellular biophysics for controlling angiogenesis and blood vessel remodeling.
The initial flow of blood plasma across the vessel wall that may ultimately trigger angiogenesis is regulated by the mechanical junctions between endothelial cells that line blood vessel walls. This research aims to establish a fundamental understanding of the role of endothelial cell interactions and remodeling in mediating the early stage mechanisms that lead to local plasma leakage, which could ultimately provide novel mechanisms for controlling pathological angiogenesis.
