Multiscale Modeling of Aortic Homeostasis

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PROJECT SUMMARY. Mechanical homeostasis is a process by which the vasculature adapts to changes in blood flow, blood pressure, and other influences. Mounting evidence suggests that compromised or lost homeostasis is a cause or consequence of many vascular diseases. There is, therefore, a pressing need for an increased understanding of vascular homeostasis, which necessarily derives from molecular and cellular processes but manifests at the tissue level via negative feedback that can be described mathematically. The goal of this project is to use an existing extensive data set on aortic remodeling in a unique mouse model of hypertension to inform and validate a new multiscale model of vascular homeostasis. Once achieved, such a model promises to help delineate compensatory mechanisms that promote tissue homeostasis via changes in cell signaling versus pathologic mechanisms that prevent homeostasis. Toward this end, we will meld recent advances in cell signaling models and continuum level growth and remodeling models to describe and predict data from a unique mouse model of hypertension wherein aortic remodeling is adaptive because of a preserved contractile phenotype and augmented synthetic phenotype, with inherently low inflammation. In this way we will avoid the typical complication of inflammation that is present in other mouse models of hypertension and drives the response away from homeostasis. We will inform our mechanobiologically motivated multiscale model using a combination of data from RNA sequencing, quantitative histology, and biaxial biomechanical (passive and active) data. Importantly, this data-informed model will enable us to explore, for the first time, the potentially adaptive versus maladaptive changes in cell signaling topology that promote or prevent effective homeostasis, thus representing a paradigm shift in the way some vascular diseases are understood and how best to treat them. Hypertension, for example, is rampant in this country and is a key risk factor for diverse cardiovascular, neurovascular, and renovascular diseases. This work is significant biologically for it has potential to provide new insight into this insidious risk factor. More generally, however, tissue homeostasis is fundamental to many different tissues and organs and our general computational approach promises to be generally applicable. Finally, this work is highly innovative for it will identify a new computational framework for integrating information across scales from differentially expressed genes to tissue-level manifestations, and it will enable delineation of potentially homeostatic versus non-homeostatic responses to diverse genetic mutations or small molecule interventions, which can guide therapeutic intervention. This proposal is submitted via the R03 mechanism since its focus is “Development of research methodology” and “Secondary analysis of existing data”, specifically, a unique multiscale data set obtained from a fortuitously discovered mouse model. It will also support the training of a promising young female biomathematician as she transitions to vascular research.