title: Smooth muscle cell-specific Tgfbr1 deficiency attenuates neointimal hyperplasia but promotes an undesired vascular phenotype for injured arteries.
abstract: Neointimal hyperplasia (NIH) and inward wall remodeling cause arterial restenosis and failure of bypass vein grafts. Previous studies from our group suggest that transforming growth factor (TGF) β promotes these pathologies via regulating cell kinetics at the early stage and matrix metabolism at the late stage. Although these temporal TGFβ effects may result from its signaling in different cell groups, the responsible cell type has not been identified. In the current study, we evaluated the effect of smooth muscle cell (SMC)-specific TGFβ signaling through its type I receptor TGFBR1 on NIH and wall remodeling of the injured femoral arteries (FAs). An inducible Cre/loxP system was employed to delete SMC Tgfbr1 (Tgfbr1iko). Mice not carrying the Cre allele (Tgfbr1f/f) served as controls. The injured FAs were evaluated on d3, d7, and d28 postoperatively. Tgfbr1ikoattenuated NIH by 92%, but had insignificant influence on arterial caliber when compared with Tgfbr1f/fcontrols on d28. This attenuation correlated with greater cellularity and reduced collagen content. Compared with Tgfbr1f/fFAs, however, Tgfbr1ikoFAs exhibited persistent neointimal cell proliferation and cell apoptosis, with both events at a greater rate on d28. Tgfbr1ikoFAs additionally contained fewer SMCs and more inflammatory infiltrates in the neointima and displayed a thicker adventitia than did Tgfbr1f/fFAs. More MMP9 proteins were detected in the adventitia of Tgfbr1ikoFAs than in that of Tgfbr1f/fcontrols. Our results suggest that disruption of SMC Tgfbr1 inhibits arterial NIH in the short term, but the overall vascular phenotype may not favor long-term performance of the injured arteries.
authors.affiliation: Division of Vascular Surgery and Endovascular Therapy, University of Florida College of Medicine, Gainesville, Florida.|Department of Surgery, Central South University Xiangya Hospital, Changsha, Hunan, China.
authors.forename: Mingmei
authors.initials: M
authors.lastname: Liao
authors.affiliation: Department of Surgery, Central South University Xiangya Hospital, Changsha, Hunan, 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, Florida.
authors.forename: Fen
authors.initials: F
authors.lastname: Wang
authors.affiliation: Division of Vascular Surgery and Endovascular Therapy, University of Florida College of Medicine, Gainesville, Florida.|Malcom Randall VA Medical Center, Gainesville, Florida.
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, Florida.
authors.forename: Yasmin H
authors.initials: YH
authors.lastname: Ali
authors.affiliation: Division of Vascular Surgery and Endovascular Therapy, University of Florida College of Medicine, Gainesville, Florida.
authors.forename: Kelvin L
authors.initials: KL
authors.lastname: Chan
authors.affiliation: Division of Vascular Surgery and Endovascular Therapy, University of Florida College of Medicine, Gainesville, Florida jiangzh@surgery.ufl.edu.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Jiang
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D005263:Femoral Artery / Q000378:metabolism / Q000473:pathology*; D017353:Gene Deletion; D006965:Hyperplasia / Q000235:genetics / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D058426:Neointima / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D014652:Vascular Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D003094:Collagen; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625842:Tgfbr1 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
keywords: Arterial restenosis; inducible gene deletion; receptor; transforming growth factor β; vascular phenotype