Novel Organ Culture &Theory for Arteriolar Remodeling

Texas A&M University System, College Station TX

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Abstract

Continued advances in our understanding of vascular mechanobiology demand comparable advances in vascular mechanics. Indeed, although there have been many separate advances in cell and tissue mechanics, there remains a pressing need for a mathematical framework that allows information to be integrated across subcellular, cellular, and tissue-levels. We submit that a potentially important step toward this goal can be achieved by combining and exploiting three recent advances in our separate laboratories. In particular, we have shown that isolated arterioles exhibit marked structural and functional remodeling over periods as short as 4 hours; we have developed a novel computer-controlled organ culture system for ex vivo studies of small vessels (mouse carotids) that are subjected to well-controlled pressures, flows, and axial stretches; and we have developed a new theoretical framework for modeling growth and remodeling of soft tissues by combining relations for the stress response with kinetic relations for the turnover of individual constituents in stressed configurations. We propose here to modify the design of our ex vivo perfusion system to allow tests on smaller vessels (isolated arterioles) while combining the system with multiphoton microscopy to enable us to study short-term remodeling on-line at subcellular, cellular, and tissue levels for periods up to 48-72 hours. Advantages of studying arterioles are that they exhibit a strong myogenic response and they consist of a contiguous outer layer of smooth muscle that can be imaged both grossly and intra-cellularly while the vessel is maintained in its native geometry and subjected to native loads, and while the cells maintain native cell-cell and cell-matrix interactions. Moreover, thin-walled arterioles admit a simpler 2-D theoretical framework based on statically determinate equilibrium equations. This utility and feasibility of this novel experimental-theoretical approach will be demonstrated by quantifying remodeling in isolated arterioles during (a) sustained contractions that are induced by the infusion of norepinephrine and angiotensin-II, (b) sustained myogenic contractions against an elevated pressure, and (c) sustained contractions in the presence of specific integrin blockers. We will collect simultaneous pressure-diameter, cell morphological, and actin cytoskeletal data at multiple times during the remodeling, which in turn will allow us to develop a novel, single theoretical framework.