Tgfbr2 disruption in SMCs leads to loss of basal Smad signaling, decreased expression and activity of contractile molecules (via MYPT1 for effects on MLC), and altered stress-related signaling (e.g., of the MAPKs p38 and ERK1/2) likely due to altered hemodynamic stress sensing through cytoskeleton/integrin/extracellular matrix links. Increased TGF-β may be a compensatory response to diminished p-Smad2 signaling and/or a direct effect of altered mechanical stress. Additional stress-induced mediators may include reactive oxygen species and cytokines as found in other models of arterial remodeling (45). Paracrine effects (blue arrows) by secreted soluble molecules from medial cells activate adventitial fibroblasts, leading to increased collagen accumulation, growth factor production (e.g., IGF1), and fibroblast proliferation. Adventitial thickening may represent a reparative “injury” response and contribute to mural integrity. Reciprocal paracrine effects (blue arrows) on medial cells by adventitial-derived mediators contribute to increased mTOR signaling and SMC proliferation that exacerbate stress-related responses. The outcome of these transcompartmental interactions is maladaptive cellular and extracellular matrix remodeling; disease manifests as aortic dilatation and/or dissection. We tested this hypothesis with several pharmacological and blocking antibody reagents (red font), all of which modulated the phenotype. Additional studies are required to validate the concept of altered stress sensing after Tgfbr2 disruption as recently reported for Acta2-deficient mice in which loss of SMA leads to increased focal adhesion kinase signaling resulting in MAPK activation and autonomous SMC proliferation (30). Possible further interactions with endothelial cells and circulating/resident leukocytes were not considered.