title: Smooth muscle cell-specific Tgfbr1 deficiency promotes aortic aneurysm formation by stimulating multiple signaling events.
abstract: 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.
authors.affiliation: Division of Vascular Surgery and Endovascular Therapy, University of Florida College of Medicine, Gainesville, FL 32610, United States.|Department of Surgery, Central South University Xiangya Hospital, Changsha, Hunan, P.R. China.
authors.forename: Pu
authors.initials: P
authors.lastname: Yang
authors.affiliation: Division of Vascular Surgery and Endovascular Therapy, University of Florida College of Medicine, Gainesville, FL 32610, United States.
authors.forename: Bradley M
authors.initials: BM
authors.lastname: Schmit
authors.affiliation: Division of Vascular Surgery and Endovascular Therapy, University of Florida College of Medicine, Gainesville, FL 32610, United States.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Fu
authors.affiliation: Division of Vascular Surgery and Endovascular Therapy, University of Florida College of Medicine, Gainesville, FL 32610, United States.
authors.forename: Kenneth
authors.initials: K
authors.lastname: DeSart
authors.affiliation: Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, FL 32610, United States.
authors.forename: S Paul
authors.initials: SP
authors.lastname: Oh
authors.affiliation: Division of Vascular Surgery and Endovascular Therapy, University of Florida College of Medicine, Gainesville, FL 32610, United States.|Malcom Randall VA Medical Center, Gainesville, FL 32608, United States.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Berceli
authors.affiliation: Division of Vascular Surgery and Endovascular Therapy, University of Florida College of Medicine, Gainesville, FL 32610, United States.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Jiang
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001014:Aortic Aneurysm / Q000235:genetics* / Q000378:metabolism; D017353:Gene Deletion; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D011945:Receptors, Angiotensin / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism
chemical_list: D011945:Receptors, Angiotensin; D018125:Receptors, Transforming Growth Factor beta; D000804:Angiotensin II; D017346:Protein Serine-Threonine Kinases; D048052:Mitogen-Activated Protein Kinase 3; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; C000625842:Tgfbr1 protein, mouse; D007703:Peptidyl-Dipeptidase A