Angiogenesis, in which endothelial cells (ECs) form new blood vessels from pre-existing ones, is a central component of tissue development, wound healing, and cancer progression. ECs engaged in angiogenesis must negotiate and integrate a complex array of extracellular stimuli: adhesive signals, soluble factors, and mechanical stiffness are known or implicated to have critical roles. ECs integrate extracellular stimuli in concert, so it has been difficult to decouple the contributions of characteristics such as stiffness from other pericellular effectors. What is needed is an experimental system that can be used to independently vary ECM components to allow for the investigation of fundamental EC-mediated angiogenic processes. In this work, we develop and apply a synthetic hydrogel system that can be used to separate and assess the contribution of each of these factors independently. We first examine the effect of stiffness on ex vivo and in vitro models of angiogenesis and the angiogenic phenotype while holding adhesivity constant We have found that angiogenesis exhibits cl biphasic response to stiffness, with gels that are too stiff or too soft unable to support angiogenesis. We next test the hypothesis that stiffness is potentiating the expression of proteolytic enzymes from the matrix metalloproteinase (MMP) family. Finally, we further test our model by holding both adhesivity and stiffness constant and instead varying the MMP-susceptibility of our hydrogel. We will use MMP-inhibition studies to implicate the specific MMPs involved in these remodeling processes. Angiogenesis is a natural process by which new blood vessels form from preexisting ones in growing tissues. However, this natural process is also known to have aberrant effects in human diseases such as cancer and diabetes. The goal of this project is to, at a fundamental level, understand the cellular events and chemical communication involved in this process which will ultimately allow the development of new disease therapies.
| Legant, Wesley R; Choi, Colin K; Miller, Jordan S et al. (2013) Multidimensional traction force microscopy reveals out-of-plane rotational moments about focal adhesions. Proc Natl Acad Sci U S A 110:881-6 |
| Miller, Jordan S; Stevens, Kelly R; Yang, Michael T et al. (2012) Rapid casting of patterned vascular networks for perfusable engineered three-dimensional tissues. Nat Mater 11:768-74 |
