Postnatal Deletion of the Type II Transforming Growth Factor-β Receptor in Smooth Muscle Cells Causes Severe Aortopathy in Mice.
OBJECTIVE
Prenatal deletion of the type II transforming growth factor-β (TGF-β) receptor (TBRII) prevents normal vascular morphogenesis and smooth muscle cell (SMC) differentiation, causing embryonic death. The role of TBRII in adult SMC is less well studied. Clarification of this role has important clinical implications because TBRII deletion should ablate TGF-β signaling, and blockade of TGF-β signaling is envisioned as a treatment for human aortopathies. We hypothesized that postnatal loss of SMC TBRII would cause aortopathy.


RESULTS
We generated mice with either of 2 tamoxifen-inducible SMC-specific Cre (SMC-CreER(T2)) alleles and homozygous floxed Tgfbr2 alleles. Mice were injected with tamoxifen, and their aortas examined 4 and 14 weeks later. Both SMC-CreER(T2) alleles efficiently and specifically rearranged a floxed reporter gene and efficiently rearranged a floxed Tgfbr2 allele, resulting in loss of aortic medial TBRII protein. Loss of SMC TBRII caused severe aortopathy, including hemorrhage, ulceration, dissection, dilation, accumulation of macrophage markers, elastolysis, abnormal proteoglycan accumulation, and aberrant SMC gene expression. All areas of the aorta were affected, with the most severe pathology in the ascending aorta. Cre-mediated loss of SMC TBRII in vitro ablated both canonical and noncanonical TGF-β signaling and reproduced some of the gene expression abnormalities detected in vivo.


CONCLUSIONS
SMC TBRII plays a critical role in maintaining postnatal aortic homeostasis. Loss of SMC TBRII disrupts TGF-β signaling, acutely alters SMC gene expression, and rapidly results in severe and durable aortopathy. These results suggest that pharmacological blockade of TGF-β signaling in humans could cause aortic disease rather than prevent it.
From the Department of Medicine, University of Washington School of Medicine, Seattle, WA (J.H.H., H.W., M.J., N.A., L.D., S.N.A., J.Y., J.K.A., K.F., A.S., R.E., D.A.D); and the Matrix Biology Program at the Benaroya Research Institute, Seattle, WA (I.K., T.N.W.).
Jie Hong
JH
Hu
From the Department of Medicine, University of Washington School of Medicine, Seattle, WA (J.H.H., H.W., M.J., N.A., L.D., S.N.A., J.Y., J.K.A., K.F., A.S., R.E., D.A.D); and the Matrix Biology Program at the Benaroya Research Institute, Seattle, WA (I.K., T.N.W.).
Hao
H
Wei
From the Department of Medicine, University of Washington School of Medicine, Seattle, WA (J.H.H., H.W., M.J., N.A., L.D., S.N.A., J.Y., J.K.A., K.F., A.S., R.E., D.A.D); and the Matrix Biology Program at the Benaroya Research Institute, Seattle, WA (I.K., T.N.W.).
Mia
M
Jaffe
From the Department of Medicine, University of Washington School of Medicine, Seattle, WA (J.H.H., H.W., M.J., N.A., L.D., S.N.A., J.Y., J.K.A., K.F., A.S., R.E., D.A.D); and the Matrix Biology Program at the Benaroya Research Institute, Seattle, WA (I.K., T.N.W.).
Nathan
N
Airhart
From the Department of Medicine, University of Washington School of Medicine, Seattle, WA (J.H.H., H.W., M.J., N.A., L.D., S.N.A., J.Y., J.K.A., K.F., A.S., R.E., D.A.D); and the Matrix Biology Program at the Benaroya Research Institute, Seattle, WA (I.K., T.N.W.).
Liang
L
Du
From the Department of Medicine, University of Washington School of Medicine, Seattle, WA (J.H.H., H.W., M.J., N.A., L.D., S.N.A., J.Y., J.K.A., K.F., A.S., R.E., D.A.D); and the Matrix Biology Program at the Benaroya Research Institute, Seattle, WA (I.K., T.N.W.).
Stoyan N
SN
Angelov
From the Department of Medicine, University of Washington School of Medicine, Seattle, WA (J.H.H., H.W., M.J., N.A., L.D., S.N.A., J.Y., J.K.A., K.F., A.S., R.E., D.A.D); and the Matrix Biology Program at the Benaroya Research Institute, Seattle, WA (I.K., T.N.W.).
James
J
Yan
From the Department of Medicine, University of Washington School of Medicine, Seattle, WA (J.H.H., H.W., M.J., N.A., L.D., S.N.A., J.Y., J.K.A., K.F., A.S., R.E., D.A.D); and the Matrix Biology Program at the Benaroya Research Institute, Seattle, WA (I.K., T.N.W.).
Julie K
JK
Allen
From the Department of Medicine, University of Washington School of Medicine, Seattle, WA (J.H.H., H.W., M.J., N.A., L.D., S.N.A., J.Y., J.K.A., K.F., A.S., R.E., D.A.D); and the Matrix Biology Program at the Benaroya Research Institute, Seattle, WA (I.K., T.N.W.).
Inkyung
I
Kang
From the Department of Medicine, University of Washington School of Medicine, Seattle, WA (J.H.H., H.W., M.J., N.A., L.D., S.N.A., J.Y., J.K.A., K.F., A.S., R.E., D.A.D); and the Matrix Biology Program at the Benaroya Research Institute, Seattle, WA (I.K., T.N.W.).
Thomas N
TN
Wight
From the Department of Medicine, University of Washington School of Medicine, Seattle, WA (J.H.H., H.W., M.J., N.A., L.D., S.N.A., J.Y., J.K.A., K.F., A.S., R.E., D.A.D); and the Matrix Biology Program at the Benaroya Research Institute, Seattle, WA (I.K., T.N.W.).
Kate
K
Fox
From the Department of Medicine, University of Washington School of Medicine, Seattle, WA (J.H.H., H.W., M.J., N.A., L.D., S.N.A., J.Y., J.K.A., K.F., A.S., R.E., D.A.D); and the Matrix Biology Program at the Benaroya Research Institute, Seattle, WA (I.K., T.N.W.).
Alexandra
A
Smith
From the Department of Medicine, University of Washington School of Medicine, Seattle, WA (J.H.H., H.W., M.J., N.A., L.D., S.N.A., J.Y., J.K.A., K.F., A.S., R.E., D.A.D); and the Matrix Biology Program at the Benaroya Research Institute, Seattle, WA (I.K., T.N.W.).
Rachel
R
Enstrom
From the Department of Medicine, University of Washington School of Medicine, Seattle, WA (J.H.H., H.W., M.J., N.A., L.D., S.N.A., J.Y., J.K.A., K.F., A.S., R.E., D.A.D); and the Matrix Biology Program at the Benaroya Research Institute, Seattle, WA (I.K., T.N.W.). ddichek@uw.edu.
David A
DA
Dichek
D000367:Age Factors; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D004549:Elastin / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000172:deficiency* / Q000235:genetics; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D004549:Elastin; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II
alleles; aortic aneurysm; homeostasis; tamoxifen; transforming growth factors