TRANSFORMING GROWTH-FACTOR-BETA-1 EXPRESSION AND MYOFIBROBLAST FORMATION DURING ARTERIAL REPAIR

Transforming growth factor-beta 1 (TGF-beta 1) plays a central role in tissue repair owing to its modulating effects on cell growth and the synthesis of extracellular matrix. We have previously shown that adven titial fibroblasts differentiate to myofibroblasts after endoluminal i njury, thereby contributing to arterial remodeling. Since TGF-beta 1 e xerts several biologic actions attributed to myofibroblasts, we examin ed its role in myofibroblast formation in a porcine model of balloon o verstretch coronary artery injury. TGF-beta 1 transcripts were induced in numerous adventitial cells 2 days after injury (47+/-10%, P<.001 v ersus control). These cells displayed no smooth muscle (SM) markers, i e, alpha-SM actin or desmin, which suggested their fibroblastic origin . This was further corroborated by the rare presence of macrophages in the injured adventitia (3+/-1%). At 7 to 8 days, most TGF-beta 1-expr essing cells demonstrated alpha-SM actin immunoreactivity. Their myofi broblast phenotype was confirmed by electron microscopy, which reveale d microfilaments (stress fibers) and a well-developed rough endoplasmi c reticulum. The distribution of TGF-beta 1 transcripts by in situ hyb ridization was paralleled by the immunolocalization of intracellular a nd extracellular TGF-beta 1 epitopes. At later times (>14 days after i njury), the decrease in TGF-beta 1 coincided with the disappearance of adventitial myofibroblasts, whereas the neointima exhibited longer TG F-beta 1 expression. In conclusion temporal and spatial relationships between TGF-beta 1 and myofibroblast formation suggest an important ro le for autocrine TGF-beta 1 in the phenotypic modulation of vascular f ibroblasts. Induction of TGF-beta 1 expression may provide a different iation signal for adventitial fibroblasts to become myofibroblasts, wh ich affect arterial remodeling via their mechanical and synthetic prop erties.