Postnatal Deletion of the Type II Transforming Growth Factor-β Receptor in Smooth Muscle Cells Causes Severe Aortopathy in Mice

Abstract

Objective Prenatal deletion of the type II 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. Approach and Results We generated mice with either of two tamoxifen-inducible SMC-specific Cre (SMC-CreERT2) alleles and homozygous floxed Tgfbr2 alleles. Mice were injected with tamoxifen, and their aortas examined 4 and 14 weeks later. Both SMC-CreERT2 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 pharmacologic blockade of TGF-β signaling in humans could cause aortic disease rather than prevent it.

Insights into ascending aortic aneurysm pathogenesis using in vivo and ex vivo imaging systems in angiotensin II-infused mice

“…It is worth noting that the outer laminae orientation of ascending aortic pathology is not a unique feature in Ang II-infused mice. This feature has been frequently observed in many animal models in which ascending aortic aneurysmal diseases are provoked by a wide variety of stimuli (7,(15)(16)(17). Of clinical relevance, the predominance of pathology in the outer medial layers is also a common feature in human ascending aortic aneurysm and dissection (14,18).…”

TGF-β (Transforming Growth Factor-β) Signaling Protects the Thoracic and Abdominal Aorta From Angiotensin II-Induced Pathology by Distinct Mechanisms

“…11, 12 In addition, we recently reported that loss of physiologic TGF-β signaling in aortic smooth muscle cells (SMC) of young mice caused significant abdominal aortic dilation and inflammation. 13 Taken together, the preponderance of experimental data support a protective role for TGF-β in AAA development and suggest that this protective role might be exploited for the development of human therapies.…”

“…In contrast, our study suggests that disruption of TGF-β signaling that is confined to SMC is sufficient to cause medial cell loss, aortic dilation, and inflammatory cell infiltration in the aortic wall. 13 …”

“…According to this hypothesis, destructive inflammatory responses generated by systemic neutralization of TGF-β in the Ang-II AAA model 11 are all caused by stimulation of the immune system by SMC that are injured by withdrawal of TGF-β signaling. We used the Ang II-induced AAA model 14 and mice with conditional alleles for the type II TGF-β receptor (TBRII) 13, 15 to test whether SMC-specific loss of TGF-β signaling accelerates AAA formation equivalently to systemic neutralization of TGF-β activity. Because Ang-II infusion also causes thoracic aortic dilation, 16, 17 we also examined thoracic aortas of the experimental mice.…”

New Mouse Model of Abdominal Aortic Aneurysm

“…19 Our own group found that loss of VSMC TGF-β signaling by type II TGF-β receptor deletion caused medial thinning in abdominal aortas of angiotensin II-infused mice. 20 Viral vector-mediated overexpression of TGF-β1 stabilized AAA in an animal xenograft model. 21 Therefore, all studies except one support a protective role for TGF-β in animal models of acute AAA formation.…”