Blockade of TGF-β (Transforming Growth Factor Beta) Signaling by Deletion of <i>Tgfbr2</i> in Smooth Muscle Cells of 11-Month-Old Mice Alters Aortic Structure and Causes Vasomotor Dysfunction—Brief Report

Abstract

Background: To test the hypothesis that smooth muscle cell (SMC) TGF-β (transforming growth factor beta) signaling contributes to maintenance of aortic structure and function beyond the early postnatal period. Methods: We deleted the TBR2 (type 2 TGF-β receptor) in SMC of 11-month-old mice (genotype Acta2 -CreER T2+/0 Tgfbr2 f/f , termed TBR2 SMΔ ) and compared their ascending aorta structure and vasomotor function to controls ( Acta2 -CreER T20/0 Tgfbr2 f/f , termed TBR2 f/f ). Results: We confirmed loss of aortic SMC TBR2 by immunoblotting. Four weeks after SMC TBR2 loss, TBR2 SMΔ mice did not have aortic rupture, ulceration, dissection, dilation, or evidence of medial hemorrhage. However, aortic medial area of TBR2 SMΔ mice was increased by 27% (0.14±0.01 versus 0.11±0.01 mm 2 ; P =0.01) and medial thickness was increased by 23% (40±1.9 versus 33±1.3 μm; P =0.004) compared with littermate controls. Wire myography performed on ascending aortic rings showed hypercontractility of TBR2 SMΔ aortas to phenylephrine (E max , 15.9±1.2 versus 10.8±0.7 mN; P =0.0003) and reduced relaxation and sensitivity to acetylcholine (E max , 64±14% versus 96±2%; P =0.001; −logEC 50 , 6.9±0.1 versus 7.7±0.1; P =0.0001). Neither maximal relaxation nor sensitivity to sodium nitroprusside differed (E max , 102±0.3% versus 101±0.3%; −logEC 50 , 8.0±0.04 versus 7.9±0.08; P &gt;0.4 for both). Conclusions: Loss of TGF-β signaling in aortic SMC of 1-year-old mice does not cause early severe aortopathy or death; however, it causes mild structural and substantial physiological abnormalities. SMC TGF-β signaling plays an important role in maintaining aortic homeostasis in older mice. This role should be considered in the design of clinical studies that aim to prevent aortopathy by blocking SMC TGF-β signaling.

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