Smooth muscle cell-specific Tgfbr1 deficiency promotes aortic aneurysm formation by stimulating multiple signaling events

• Published in: Scientific reports 2016-10, Vol.6 (1), p.35444-35444, Article 35444
• Main Authors: Yang, Pu, Schmit, Bradley M., Fu, Chunhua, DeSart, Kenneth, Oh, S. Paul, Berceli, Scott A., Jiang, Zhihua
• Format: Article
• Language: English
• Subjects: 41; 45/41; 631/443/592/75; 631/80/86; Aneurysms; Angiotensin; Angiotensin II; Angiotensin II - metabolism; Animals; Aorta - metabolism; Aorta - pathology; Aortic Aneurysm - genetics; Aortic Aneurysm - metabolism; Aortic aneurysms; Clonal deletion; Degeneration; Gene Deletion; Homeostasis; Humanities and Social Sciences; Male; MAP Kinase Signaling System; Maturation; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase 3 - metabolism; multidisciplinary; Myocytes, Smooth Muscle - metabolism; Pathology; Peptidyl-Dipeptidase A - metabolism; Phosphorylation; Protein-Serine-Threonine Kinases - deficiency; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Receptors, Angiotensin - metabolism; Receptors, Transforming Growth Factor beta - deficiency; Receptors, Transforming Growth Factor beta - genetics; Receptors, Transforming Growth Factor beta - metabolism; Science; Smooth muscle; Thorax
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep35444

Transforming growth factor (TGF)-β signaling disorder has emerged as a common molecular signature for aortic aneurysm development. The timing of postnatal maturation plays a key role in dictating the biological outcome of TGF-β signaling disorders in the aortic wall. In this study, we investigated the impact of deficiency of TGFβ receptors on the structural homeostasis of mature aortas. We used an inducible Cre-loxP system driven by a Myh11 promoter to delete Tgfbr1, Tgfbr2, or both in smooth muscle cells (SMCs) of adult mice. TGFBR1 deficiency resulted in rapid and severe aneurysmal degeneration, with 100% penetrance of ascending thoracic aortas, whereas TGFBR2 deletion only caused mild aortic pathology with low (26%) lesion prevalence. Removal of TGFBR2 attenuated the aortic pathology caused by TGFBR1 deletion and correlated with a reduction of early ERK phosphorylation. In addition, the production of angiotensin (Ang)-converting enzyme was upregulated in TGFBR1 deficient aortas at the early stage of aneurysmal degeneration. Inhibition of ERK phosphorylation or blockade of AngII type I receptor AT1R prevented aneurysmal degeneration of TGFBR1 deficient aortas. In conclusion, loss of SMC- Tgfbr1 triggers multiple deleterious pathways, including abnormal TGFBR2, ERK, and AngII/AT1R signals that disrupt aortic wall homeostasis to cause aortic aneurysm formation.