Vein graft failure (VGF) following coronary artery bypass grafting occurs through proliferation and migration of vascular smooth muscle cells (VSMC) forming a neointima that blocks the graft lumen. Dysregulated renin angiotensin system (RAS) signalling promotes vascular remodelling through angiotensin II (Ang II) stimulating the angiotensin type 1 receptor. The counter-regulatory RAS peptide angiotensin-(1–9) [Ang-(1–9)], acts via the angiotensin type 2 receptor and inhibits VSMC proliferation and migration.1 Here, gene transfer of Ang-(1–9) was investigated as a novel therapy to inhibit human saphenous vein VSMC (HSVSMC) migration and proliferation in vitro and neointima formation in vivo.
An adenoviral vector [RAdAng-(1–9)] was generated expressing a fusion protein that secretes Ang-(1–9) extracellularly following transduction.2 Transgene expression was confirmed by immunoblotting. HSVSMC migration was evaluated by scratch wound assay. MTS assay was used to determine effects of conditioned media from RAdAng-(1–9) transduced HepG2 cells on HSVSMC proliferation.
Saline, RAdControl or RAdAng-(1–9) (1 × 1011 vp) was administered to C57/Bl6 mice intravenously. After 48 hours the endothelium of the left carotid arteries was denuded by wire injury. After 4 weeks, injured carotid arteries were subjected to histological staining and morphometric analysis performed.
Immunoblotting of cell lysates and conditioned media demonstrated RAdAng-(1–9)-transduced HSVSMC expressed and secreted the fusion protein. RAdAng-(1–9) transduction of HSVSMC inhibited Ang II-induced migration as compared to RAdControl transduced cells [p<0.001]. Treating HSVSMC with conditioned media of RAdAng-(1–9) transduced HepG2 cells inhibited proliferation [p<0.05]. RAdAng-(1–9) delivered intravenously 48 hours before surgery significantly inhibited neointima formation 28 days after carotid wire injury [p<0.001].
These data demonstrate that adenoviral gene therapy with Ang-(1–9) can be used to inhibit HSVSMC migration and proliferation and neointima formation after acute vascular injury in mice.
. McKinney, et al. Heart2015.
. Flores-Munoz, et al. PLoS ONE2010.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.