Abstract 512: Angiotensin-(1-7) Attenuates PDGF-dependent Migration of Vascular Smooth Muscle Cells
Over one million percutaneous coronary intervention (PCI) procedures are performed each year and restenosis, the narrowing of the vessel lumen due to vascular damage, occurs in more than 40% of these patients. Previous studies by our laboratory demonstrated that infusion of angiotensin-(1-7) [Ang-(1-7)], an anti-proliferative peptide hormone of the renin-angiotensin system, attenuated neointimal formation after vascular injury which was associated with reduced vascular smooth muscle cell (VSMC) proliferation. However, prevention of restenosis after PCI requires inhibition of both VSMC proliferation and migration. In this study, the effect of Ang-(1-7) on VSMC migration was investigated to determine whether a decrease in VSMC migration also represents a component of the heptapeptide-induced reduction in neointimal formation. Platelet-derived growth factor (PDGF), a potent stimulus for VSMC migration, increased chemotaxis in a modified Boyden’s chamber; PDGF stimulated chemotaxis 228% over random migration and pre-treatment with Ang-(1-7) reduced the PDGF-mediated migration to 132% over random movement, a reduction of 42.1% (n=6, p<0.05). PDGF also stimulated directional migration in a wounding assay, by 600% over random migration; pre-treatment with Ang-(1-7) reduced directional migration in response to PDGF to 317% of random migration, a 40.4% decrease (n=5, p>0.01). The reduction in PDGF-mediated migration by Ang-(1-7) was associated with a significant decrease in the phosphorylation of tyrosine 1009 on the PDGF beta receptor as well as the src homology 2 phosphatase-2 (SHP-2) and the tyrosine kinase Src, two enzymes which are positive mediators of PDGF-induced migration. Pre-treatment with Ang-(1-7) attenuated the PDGF-dependent increase in the phosphoY1009-PDGF receptor by 60%, phosphoY580-SHP-2 by 56% and phosphoY416-Src by 45% (n=5, p<0.05). These data demonstrate that Ang-(1-7) inhibits VSMC migration to attenuate neointimal formation, which may result from a reduction in the phosphorylation of the PDGF receptor or attenuation of the cellular events resulting from receptor activation. Further, these results suggest that Ang-(1-7) may be administered as a targeted therapeutic to prevent vascular restenosis.
- © 2012 by American Heart Association, Inc.