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Mathematical Modeling of the Spatial Spread of cAMP Signals Within and Between Pulmonary Endothelial Cells
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A5723 - Mathematical Modeling of the Spatial Spread of cAMP Signals Within and Between Pulmonary Endothelial Cells
Author Block: T. C. Rich1, N. Stone2, S. Shettlesworth2, A. Phan2; 1Ctr for Lung Biology, Univ of South Alabama, Mobile, AL, United States, 2Mechanical Engineering, Univ of South Alabama, Mobile, AL, United States.
Rationale: Pulmonary endothelial cells form contiguous, semi-permeable barriers between the bloodstream and the interstitial space. The subcellular localization of cAMP synthesis governs EC barrier function. cAMP generated by endogenous, plasma membrane-localized adenylyl cyclase (AC) enhances PMVEC barrier function and limits inflammation-induced pulmonary edema and lung injury. Previous studies of cAMP signaling within ECs have focused on intracellular signals. However, the role(s) of intercellular cAMP signals and the spatial spread of cAMP signals between cells via gap junctions are not well understood. The purpose of this work is to develop finite element analysis (FEA) models that both describe intracellular and intercellular cAMP signals. FEA models are well suited to studies of the kinetics and spatial spread of second messenger signals (solving systems of partial and ordinary differential equations) and can be expanded to form multiscale models to simulate second messenger signals in the pulmonary vasculature.
Methods: Linearized equations describing the synthesis, degradation, and spatial spread of cAMP signals within and between two-dimensional arrays of ECs were developed. Finite element method was employed to discretize these linearized equations that were subsequently solved numerically using custom MATLAB scripts. ANSYS and DistMesh were utilized for mesh generation. Gap junctions were described as a cAMP transfer coefficient attributed to a shared mesh element between two cells. This approach allowed control of the amount of cAMP that diffused through a gap junction and into the adjacent cell. Results are displayed as cAMP gradients within/between cells at specific time points or as a time course at specific mesh nodes.
Results: Model simulations demonstrate that under certain conditions, sustained cAMP gradients can be formed within ECs, similar to those observed in rat pulmonary microvascular endothelial cells. Model simulations also demonstrated that intercellular transfer of cAMP would allow cAMP to spread between cells, and accumulate in near junctional borders of adjacent cells.
Conclusions: The results demonstrate that finite element models are well suited to describe the spatial spread and kinetics of cAMP signals in 2D cellular clusters. They also suggest that localized PDE activity is required to prevent the spatial spread of cAMP signals between cells interconnected by open gap junctions. The ability to expand the scale of models from isolated cells to 2D cellular arrays, and, eventually, 3D descriptions of cAMP signals within the pulmonary vasculature allows FEA models to be an effective tool for the study of second messenger signaling. (NIH P01HL066299, S10RR027535, and S10OD020149)
Author Block: T. C. Rich1, N. Stone2, S. Shettlesworth2, A. Phan2; 1Ctr for Lung Biology, Univ of South Alabama, Mobile, AL, United States, 2Mechanical Engineering, Univ of South Alabama, Mobile, AL, United States.
Rationale: Pulmonary endothelial cells form contiguous, semi-permeable barriers between the bloodstream and the interstitial space. The subcellular localization of cAMP synthesis governs EC barrier function. cAMP generated by endogenous, plasma membrane-localized adenylyl cyclase (AC) enhances PMVEC barrier function and limits inflammation-induced pulmonary edema and lung injury. Previous studies of cAMP signaling within ECs have focused on intracellular signals. However, the role(s) of intercellular cAMP signals and the spatial spread of cAMP signals between cells via gap junctions are not well understood. The purpose of this work is to develop finite element analysis (FEA) models that both describe intracellular and intercellular cAMP signals. FEA models are well suited to studies of the kinetics and spatial spread of second messenger signals (solving systems of partial and ordinary differential equations) and can be expanded to form multiscale models to simulate second messenger signals in the pulmonary vasculature.
Methods: Linearized equations describing the synthesis, degradation, and spatial spread of cAMP signals within and between two-dimensional arrays of ECs were developed. Finite element method was employed to discretize these linearized equations that were subsequently solved numerically using custom MATLAB scripts. ANSYS and DistMesh were utilized for mesh generation. Gap junctions were described as a cAMP transfer coefficient attributed to a shared mesh element between two cells. This approach allowed control of the amount of cAMP that diffused through a gap junction and into the adjacent cell. Results are displayed as cAMP gradients within/between cells at specific time points or as a time course at specific mesh nodes.
Results: Model simulations demonstrate that under certain conditions, sustained cAMP gradients can be formed within ECs, similar to those observed in rat pulmonary microvascular endothelial cells. Model simulations also demonstrated that intercellular transfer of cAMP would allow cAMP to spread between cells, and accumulate in near junctional borders of adjacent cells.
Conclusions: The results demonstrate that finite element models are well suited to describe the spatial spread and kinetics of cAMP signals in 2D cellular clusters. They also suggest that localized PDE activity is required to prevent the spatial spread of cAMP signals between cells interconnected by open gap junctions. The ability to expand the scale of models from isolated cells to 2D cellular arrays, and, eventually, 3D descriptions of cAMP signals within the pulmonary vasculature allows FEA models to be an effective tool for the study of second messenger signaling. (NIH P01HL066299, S10RR027535, and S10OD020149)
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