Chemomechanical Stimulation of Adventitial Fibroblast Remodeling of Collagen

Yale University, New Haven CT

Investigators

Abstract

The research objective of this award is to use a unique combination of cell and tissue culture approaches and nonlinear biomechanics to quantify and model the rates and extents of production and cross-linking of fibrillar collagens by adventitial fibroblasts in response to chemo-mechanical stimuli that are relevant to arterial biology and pathology. Specifically, aortic fibroblasts will be subjected to three different classes of biaxial loading and their responses quantified as a function of exposure to two potent vasoactive molecules that are released by vascular endothelial cells in response to changes in blood flow and two potent enzymatic cross-linkers of collagen to elucidate effects of these four biomolecules on overall tissue pre-stress, anisotropy, and stiffness. These responses will be compared to those of aortic smooth muscle cells to delineate differences in the ability of these two allied cell types to remodel collagen. If successful, this study will yield a unique growth and remodeling computational model that should help elucidate mechanisms of arterial repair and disease progression in cases where the function of smooth muscle cells is lost (e.g., in aortic aneurysms). Smooth muscle cells and fibroblasts similarly work together to promote the function of many other tissues, including airways, the gastrointestinal tract, and the urinary tract, and they can be used separately or together in building tissue engineered constructs. Understanding responses by these two cell types to coupled chemomechanical stimulation will thus have broad implications. The impact of this work will be broadened by publishing the findings in diverse journals, in an undergraduate biomechanics and biotransport textbook that is in advanced preparation, and on the IUPS Physiome website. One Ph.D. student and multiple undergraduate researchers will receive unique interdisciplinary training in experimental and computational mechanobiology.