Integrative Mechanobiological Understanding of Effects of Hypertension and Exercise on Thoracic Aortopathy

Yale University, New Haven CT

Investigators

Abstract

PROJECT SUMMARY – PROJECT 4 Hypertension is a major risk factor for thoracic aortopathy and anti-hypertensive medications are commonly prescribed, though with controversy over the use of specific drugs in certain patients. Aerobic exercise provides tremendous cardiovascular benefit to non-aortopathy subjects, but there is controversy over appropriate levels of exercise for individuals with thoracic aortic disease. Isolated reports in the literature have studied the potential benefits of anti-hypertensive treatments and exercise in single mouse models of thoracic aortopathy, but in each case with a narrow focus and inconsistent methods. Consequently, these controversies persist. We hypothesize that detailed associations of the transcriptional profile and biomechanical phenotype of the aorta will better elucidate the mechanisms by which hypertension exacerbates thoracic aortopathy as well as why particular treatments (drugs or exercise) are protective or not in cases of different predisposing genetic variants. Toward this end, we will use consistent methods to determine the transcriptional profile that drives the biomechanical phenotype of the aorta in 3 key mouse models of aortopathy that address 3 critical nodes along the mechano-biological (cell-matrix) axis that fail in thoracic aortic aneurysms and can drive dissection and possible rupture. We will study effects of 3 standard-of-care anti-hypertensive drugs in these 3 mouse models in the presence of induced hypertension to determine regulatory pathways that superimpose on those associated with the underlying predisposing variant and dictate changes in aortic structure and function. We will study effects of 2 different forms (voluntary and forced) of aerobic exercise in these same 3 mouse models in the presence of hypertension. We submit that consistent “transcript-to-tissue” level data across these many mouse models, as a function of sex as a biological variable, will complement well the studies in Projects 1-3 as well as Project 5, thus overcoming the prior narrow focus and inconsistent methods employed by different labs that has prevented integrative understanding of thoracic aortopathy and its treatment. Finally, given the large PPG-wide data base, we will develop 2 data-informed (differential equation based) computational models to complement the data- driven (neural network based) algorithm of Core B to integrate findings across mouse models in this Project as well as across Projects 1-3. These computations will enable novel integrative understanding of the molecular, cellular, and biomechanical mechanisms that drive thoracic aortopathy while providing unique insight into possible new approaches for treatment. This Project is significant given the increasing morbidity and mortality associated with thoracic aortopathy in women and men; it is innovative in its consistent quantification of the transcriptionally driven biomechanical phenotype across diverse mouse models and its use of advanced computational models to integrate findings across predisposing variants, risk factors, and potential treatments.