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.
Highlights
Neointimal hyperplasia (NIH) and inward wall remodeling develop in stented arteries and vein bypass grafts and frequently cause failure of these revascularization procedures
We have previously reported that Tgfbr1iko aortas develop spontaneous aortic aneurysms, with the structural defects becoming evident on d13 (Schmit et al 2015)
Tgfbr1iko femoral arteries (FAs) were indistinguishable from Tgfbr1f/f FAs when evaluated with the measurements of external elastic lamina (EEL) area (P = 0.621), medial thickness (P = 0.857), and fraction of a-actin cells (P = 0.812) in the tunica media (Fig. 1B–D)
Summary
Neointimal hyperplasia (NIH) and inward wall remodeling develop in stented arteries and vein bypass grafts and frequently cause failure of these revascularization procedures. In response to wall injury, SMCs lose their contractile property and acquire a synthetic phenotype that enables them to synthesize a plethora of growth factors, proinflammatory cytokines and chemokines, and proteases (Owens et al 2004). These bioactive substances, in turn, act on SMCs themselves and other cell groups, amplifying the local inflammatory response (Bobik 2006). Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.
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