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 TGF β 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 TGF β 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 (Tgfbr1 iko). Mice not carrying the Cre allele (Tgfbr1 f/f) served as controls. The injured FAs were evaluated on d3, d7, and d28 postoperatively. Tgfbr1 iko attenuated NIH by 92%, but had insignificant influence on arterial caliber when compared with Tgfbr1 f/f controls on d28. This attenuation correlated with greater cellularity and reduced collagen content. Compared with Tgfbr1 f/f FAs, however, Tgfbr1 iko FAs exhibited persistent neointimal cell proliferation and cell apoptosis, with both events at a greater rate on d28. Tgfbr1 iko FAs additionally contained fewer SMCs and more inflammatory infiltrates in the neointima and displayed a thicker adventitia than did Tgfbr1 f/f FAs. More MMP9 proteins were detected in the adventitia of Tgfbr1 iko FAs than in that of Tgfbr1 f/f controls. 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.

Promoters to Study Vascular Smooth Muscle

“…This limitation is profound as SMCs are key players in cardiovascular development and disease, and cardiovascular disease is the leading cause of death in women. Notably, the laboratory of Zhihua Jiang recently reported that through breeding they have obtained a colony of Myh11-CreER T2 mice -presumably by translocation to the X chromosome -in which the transgene is inherited by both male and female mice [29][30][31] . Importantly, this colony may markedly enhance the study of SMCs in the development and disease of female mice.…”

“…• Also marks pericytes in the lung • Y chromosomal transgene limits study to males • (Jiang lab variant line expresses in male and female [29][30][31] )…”

Systems Pharmacology Dissection of Mechanisms of Dengzhan Xixin Injection against Cardiovascular Diseases

“…Most of these targets predicted in our research are involved in vascular systems. For instances, Cathepsin B (CTSB) is a proteolytic enzyme potentially modulating angiogenic processes and extracellular matrix remodeling 46) ; ESR1 medi-ates the vascular system to promote the functional recovery of vascular injury 47) ; Cell-specific TGFBR1 deficiency of smooth muscle attenuates neointimal hyperplasia but promotes an undesired vascular phenotype for injured arteries 48) ; F2, F7 and F10 are concerned with thrombosis 49) ; PPARG, ADAM17 and GSK3B is relevant to ischemic and inflammation processes [50][51][52] ; NOS3 produces nitric oxide (NO) in endothelium, which mediates vasodilation. 53) Accumulating evidence suggests that MAPKs (MAPK10 and MAPK8) are related to cardiac diseases, such as myocardial infarction (ischemia), hypertrophy and heart failure.…”