Thoracic aortic aneurysms (TAAs) are a group of life-threatening conditions driven by complex pathophysiological interactions among different cell types, distinct extracellular matrix (ECM) compartments and multiple biochemical signals that, together, predispose the vessel wall to dissection and rupture. We hypothesize that, irrespective of the underlying cause, dysfunctional mechanobiology is a shared mechanism of TAA development and consequently, that molecules sensing, transducing or countering mechanical stress may represent potential new targets for drug therapy. This PPG focuses on identifying key disease-related cellular responses that are triggered either by experimentally increased blood pressure on a structurally normal tissue or by physiological hemodynamic load on a genetically deficient matrix. Project 1 employs a mouse model of progressively severe Marfan syndrome (MFS) to characterize the latter mechanism of arterial disease. This genetic model of TAA was chosen because the mutated protein (fibrillin-1) regulates several key aspects of arterial function and homeostasis, including tissue integrity, endothelial cell mechanotransduction, angiotensin II (AngII) type I receptor (AT1r) activity and TGF? signaling. Our proposal is organized into two specific aims that combine genetic, biomechanical and computational approaches to elucidate the primary triggers and downstream mediators and targets of AngII-dependent and AngII-independent AT1r signaling in distinct aortic compartments of MFS mice (Aim 1), and to evaluate how incremental loss of ECM integrity influences the biological responses of aortic cells to induced hypertension (Aim 2). Expected findings will inform, extend or complement the studies pursued by other PPG projects, which collectively will provide a new tissue-level understanding of the molecular factors and cellular events responsible for TAA onset and progression in a validated mouse model of lethal MFS.
Thoracic aortic aneurysm (TAA) remains an unmet medical challenge, despite significant research effort. Consonant with the overall scope of our PPG, this project will identify key upstream and downstream determinants of TAA onset and progression with the long-term intent of translating this information into effective new drug treatments.