Pharmacologically Improved Contractility Protects Against Aortic Dissection in Mice With Disrupted Transforming Growth Factor-β Signaling Despite Compromised Extracellular Matrix Properties

Abstract

Objective Transforming growth factor-beta (TGF-β) is a pleiotropic cytokine having diverse roles in vascular morphogenesis, homeostasis, and pathogenesis. Altered activity of and signaling through TGF-β has been implicated in thoracic aortic aneurysms and dissections, conditions characterized by a reduced structural integrity of the wall that associates with altered biomechanics and mechanobiology. We quantify and contrast the passive and active biaxial biomechanical properties of the ascending and proximal descending thoracic aorta in a mouse model of altered TGF-β signaling, with and without treatment with rapamycin. Approach and Results Postnatal disruption of the gene (Tgfbr2) that codes the type II TGF-β receptor compromises vessel-level contractility and elasticity. Daily treatment with rapamycin, an mTOR inhibitor that protects against aortic dissection in these mice, largely preserves or restores the contractile function while the passive properties remain compromised. Importantly, this increased smooth muscle contractility protects an otherwise vulnerable aortic wall from pressure-induced intramural delaminations in vitro. Conclusions Notwithstanding the protection afforded by rapamycin in vivo and in vitro, the residual mechanical dysfunctionality suggests a need for caution if rapamycin is to be considered as a potential therapeutic. There is a need for in vivo evaluations in cases of increased hemodynamic loading, including hypertension or extreme exercise, which could unduly stress a structurally vulnerable aortic wall. Given these promising early results, however, such studies are clearly warranted.

mTOR (Mechanistic Target of Rapamycin) Inhibition Decreases Mechanosignaling, Collagen Accumulation, and Stiffening of the Thoracic Aorta in Elastin-Deficient Mice

“…The ability of mTOR inhibitors to modulate mechanoresponses in SMCs may relate to its beneficial effects on pathological aortic remodeling and reinforce the concepts that vascular cell activation and integrin-mediated mechanotransduction play important roles in elastin aortopathy [30,31]. Additionally, mTOR inhibition increased contractile protein expression in differentiated SMCs in vivo, though to a lesser extent than previously reported for de-differentiated cultured SMCs [28] and aortas with loss of SMC differentiation due to disruption of TGF-β signaling [32,33]. …”

Role of Microvascular Tone and Extracellular Matrix Contraction in the Regulation of Interstitial Fluid

“…A recent study showed that pressure-induced intramural delamination was associated with accumulation of interstitial fluid in aortic media of mice with disrupted TGF-β signaling and could be prevented in part by pharmacological improvement of SMC contractility ex vivo. 46 The results are consistent with the present hypothesis on the role of ECM contraction in limiting interstitial fluid retention and delamination. However, further studies are needed to examine whether the same results may apply to subvessel-level SMC contraction in human thoracic aorta.…”

Killing Me Unsoftly

“…28 On the other hand, active VSMC contraction may serve as a crucial protective mechanism against aortic dissection, as recently suggested by Ferruzzi and colleagues following elegant ex vivo experiments in dissection prone murine aortas. 29 …”

“…62 Jay Humphrey’s group published a study in ATVB earlier this year demonstrating that postnatal disruption of TGF-β type II receptor Tgfbr2 in SMCs compromises both active (contractile) and passive (structural) biaxial biomechanical properties in the murine thoracic aorta. 29 Furthermore, they found that daily in vivo treatment with rapamycin largely preserves or restores biaxial contractile properties, but not passive structural properties.…”