Roles of mTOR in thoracic aortopathy understood by complex intracellular signaling interactions.

Thoracic aortopathy–aneurysm, dissection, and rupture–is increasingly responsible for significant morbidity and mortality. Advances in medical genetics and imaging have improved diagnosis and thus enabled earlier prophylactic surgical intervention in many cases. There remains a pressing need, however, to understand better the underlying molecular and cellular mechanisms with the hope of finding robust pharmacotherapies. Diverse studies in patients and mouse models of aortopathy have revealed critical changes in multiple smooth muscle cell signaling pathways that associate with disease, yet integrating information across studies and models has remained challenging. We present a new quantitative network model that includes many of the key smooth muscle cell signaling pathways and validate the model using a detailed data set that focuses on hyperactivation of the mechanistic target of rapamycin (mTOR) pathway and its inhibition using rapamycin. We show that the model can be parameterized to capture the primary experimental findings both qualitatively and quantitatively. We further show that simulating a population of cells by varying receptor reaction weights leads to distinct proteomic clusters within the population, and that these clusters emerge due to a bistable switch driven by positive feedback in the PI3K/AKT/mTOR signaling pathway. Author summary: Cell signaling drives changes across scales, from altered transcription at the single-cell level to tissue-level growth and remodeling. Studying complex interactions within cell signaling pathways can lead to a better understanding of the progression of disease. In particular, we are interested in how vascular cells can change their phenotype in a way that exacerbates aortopathy, namely, the development of aneurysms, dissections, and rupture. In this study we built a novel cell signaling network model of a vascular smooth muscle cell using archival data and used it to capture the effects of a genetic knock-out and subsequent pharmacologic rescue. We then used the model to simulate populations of smooth muscle cells and found that small perturbations to the strength of signaling can lead to distinct clusters of cells. With further analysis of the network substructures, we found that a positive feedback loop within the network was responsible for the distinct phenotypes we saw in our clusters of simulated cells. We believe that this work not only helps us to understand changes in smooth muscle cell phenotype but also opens the possibility to study other signaling perturbations associated with aortopathy. [ABSTRACT FROM AUTHOR]