Perivascular Release of Insulin-like Growth Factor-1 Limits Neointima Formation in the Balloon-injured Artery by Redirecting Smooth Muscle Cell Migration

Abstract

Insulin-like growth factor-1 (IGF-1) is a potent chemoattractant to vascular smooth muscle cells (SMCs). The authors hypothesize that perivascular release of IGF-1 in vivo can direct migration of SMCs away from the lumen and reduce neointima formation in a rabbit model of arterial balloon injury. Balloon angioplasty of the common femoral arteries was performed in adult male New Zealand White rabbits (n = 8 per treatment group) and controlled release microspheres delivering either IGF-1 or blank control treatment were implanted perivascularly at the angioplasty site prior to surgical closure. At 7 days, five arteries per group were harvested and cross-sections were subjected to anti-PCNA (proliferating cell nuclear antigen) immunostaining to determine the number and distribution of proliferating SMCs. At 28 days, the remaining three arteries per group were harvested and sections were evaluated for intima-to-media (I/M) ratios by means of VVG-Masson staining. One-way analysis of variance with Fisher protected least significant difference post hoc testing was used to determine statistical significance at P < .05. At 7 days, PCNA(+) medial SMCs assumed a significantly more peripheral (ie, further from lumen) distribution in the vessel wall with use of perivascular IGF-1 than with use of blank treatment (P < .05). Overall SMC proliferation was not significantly different, thus the change in distribution was likely due to directionally altered SMC migration. At 28 days, perivascular IGF-1 significantly decreased I/M ratios by 44% relative to control treatment (P < .05). Perivascular release of IGF-1 can directionally guide SMC migration away from the lumen and reduce neointima in the balloon-injured artery. This novel strategy might have implications in the development of antirestenosis therapies.