FIBULIN-5 & WALL STRESSES IN VASCULAR REMODELING: THEORY AND EX VIVO EXPERIMENTS

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DESCRIPTION (provided by applicant): Vascular growth and remodeling (G&R) plays a key role in many physiological (e.g., normal vascular development and aging) and pathophysiological processes (e.g., hypertension, arteriosclerosis, and aneurysms), as well as the success (or failure) of many clinical interventions (e.g., vein grafts, synthetic vascular grafts, stents, and balloon angioplasty). Despite the explosion of information on soft tissue G&R, from molecular level to the tissue and whole organism level, attempts at integrating these data into a predictive model is still in its infancy. The goal of the current proposal is to develop and test an innovative theoretical- experimental paradigm for characterizing the time-course of vascular remodeling that integrates a novel organ culture device, two-photon laser scanning microscopy (LSM), biaxial biomechanical testing, and multi-scale mathematical modeling. Our central hypothesis is that volume fractions, fiber directions, and stress-free states of elastic fibers, collagen fibers, and smooth muscle cells can be quantified via two-photon LSM in parallel with biaxial biomechanical data on live mouse CCAs and these data can be incorporated into a constrained mixture model to describe and predict temporal changes in material behavior in both normal (adaptive) and maladaptive remodeling. Whereas much attention has been paid to the role of wall shear stress and circumferential (hoop) stress in vascular remodeling, the role of axial stress has been largely overlooked. Many clinical observations, however, highlight the importance of axial remodeling in the vasculature; marked tortuousity in AAAs, mammary artery by-pass grafts, and many vessels with hypertension and aging are a few but a few examples. Elastic fibers are thought to endow arteries with their in vivo axial stain and the loss of functional elastic fibers (which occurs aneurysms, hypertension, and aging) may be associated with impaired axial remodeling and development of tortuousity. Fibulin-5 is an ECM protein that binds tropoelastin and fibrillins with ava3, ava5, and a9a1 integrins(60) to bridge elastic fibers with cells. Thus, fibulin-5 is likely a key protein involved in regulation of elastic fibers and thus key in axial remodeling. The aims of this proposal are to measure and characterize the biomechanical behavior and microstructural organization of CCAs from wild-type and fib-5-/- mice and observe and quantify the biomechanical and microstructural remodeling of CCAs from wild-type and fib-5-/- mice exposed to (a) increased axial extension (b) increase transmural pressure, or (c) combined increase in axial extension and pressure in organ culture. Successful realization of these aims will establish an innovative approach for studying vascular remodeling under normal and pathophysiological conditions that can be used gain insights toward the development clinical pathologies and the design of appropriate clinical interventions. Vascular remodeling plays a key role in many physiological (e.g., normal vascular development and aging) and pathophysiological processes (e.g., hypertension, arteriosclerosis, and aneurysms), as well as the success (or failure) of many clinical interventions (e.g., vein grafts, synthetic vascular grafts, stents, and balloon angioplasty). The purpose of this work is to develop an innovative approach for studying vascular remodeling that combines multi-scale computational modeling with tissue culture and multi-photon microscopy that can be used gain insights toward the development clinical pathologies and the design of appropriate clinical interventions.