Abstract 84: Deletion of the Type II TGF-ß Receptor in Smooth Muscle Causes Severe Aortopathy in Mice

Abstract

Introduction: Prenatal deletion of the type II TGF-beta receptor (TBRII) prevents normal vascular morphogenesis, impairs smooth muscle cell (SMC) differentiation and matrix accumulation, and results in embryonic death in mid-gestation (~embryonic day 13-14). However, the role of TBRII in adult SMC is unknown. Clarification of the postnatal role of TBRII has important clinical implications because TBRII deletion should ablate TGF-beta signaling and blockade of TGF-beta signaling is currently envisioned as a treatment for human aortopathies. Hypothesis: We hypothesized that postnatal deletion of TBRII in SMC would impair aortic homeostasis, resulting in aortopathy. Methods: We bred mice with a tamoxifen-inducible SMC-specific Cre allele and a floxed Tgfbr2 allele. Mice (6-19 wk old) were injected with tamoxifen or vehicle, and euthanized 4-14 wk later. Aortic mRNA and protein were extracted and Tgfbr2 mRNA transcripts and TBRII protein measured. Aortas were examined grossly after a thoracoabdominal incision, and a subset was examined histologically using both H&E and VVG stains. Results: There were no sudden deaths. Tamoxifen-treated doubly transgenic mice had a ~85% decrease in aortic Tgfbr2 transcripts and decreased TBRII protein on western blot. Tamoxifen-treated doubly transgenic mice exhibited several aortic pathologies, none of which were present either in vehicle-treated transgenic or tamoxifen-treated nontransgenic mice: aortic intramural hematoma (19 of 69), rare frank aortic dissection with blood in a large false lumen, penetrating aortic ulcers (7 of 9), medial thickening (46% increase; P < 0.001), aortic dilation, and adventitial thickening. Most of these pathologies were confined to the ascending aorta and arch. In descending thoracic aortas we observed occasional dilation (grossly) and consistent adventitial thickening (on histologic sections). No definite pathology was observed in abdominal aortas. Conclusions: TBRII expression in SMC plays a critical role in maintaining postnatal aortic homeostasis. Because loss of TBRII disrupts TGF-beta signaling, these results suggest that blockade of TGF-beta signaling in humans may cause aortic disease rather than prevent it.