Abstract 9: Smooth Muscle Cell Tgfbr2 Deletion in Mice Causes Aortic Hypercontractility and Impaired Endothelium-Dependent Relaxation

Background: Abnormal smooth muscle cell (SMC) TGF-β signaling is proposed as a critical driver in the development of thoracic aortic aneurysms and dissections (TAAD) associated with Marfan and Loeys-Dietz Syndromes as well as nonsyndromic TAAD. However, the mechanisms by which altered SMC TGF-β signaling causes TAAD are poorly understood. Others have proposed that loss of SMC TGF-β signaling causes TAAD by impairing SMC contractility, leading to aortic medial degeneration and dilation. However, mice generated in our lab with deficient SMC TGF-β signaling (due to SMC-specific deletion of the type II TGF-β receptor) have thicker aortic medias and increased mRNA encoding SMC contractile proteins. These observations predict increased contractility. Methods & Results: We addressed this apparent contradiction experimentally by measuring vasomotor function (by tension myography) and contractile protein expression (by immunoblotting) in aortas of mice with normal or deficient SMC TGF-β signaling. Isolated aortic rings from mice with deficient SMC TGF-β signaling showed increased contraction to phenylephrine (Emax: 13.5 mN vs 7.8 mN in controls; p Conclusion: Physiologic SMC TGF-β signaling is an important determinant of both SMC contractility and endothelial function. Disruption of physiologic SMC TGF-β signaling may lead to TAAD through direct effects on SMC as well as through indirect effects on endothelial function. Our results also suggest an unanticipated role for SMC TGF-β signaling in regulating endothelial-mediated vasomotor function.