Matricryptin p1158/59 Modulates Vascular Remodeling During Carotid Artery Bypass

Abstract

When atherosclerosis develops in the coronary arteries, blood flow is compromised and disease progression increases the risk of myocardial infarction. Saphenous vein (SV) is the most common conduit used for coronary artery bypass grafting; however, its long‐term patency and survival rates are not ideal. One year after surgery, 10% to 20% of SV grafts fail, from 1–5 years an additional 5% to 10% fail, and from 6–10 years, an added 20% to 25% fail. Early SV graft failure is mainly due to thrombosis (graft spasm) or technical error, whereas longer‐term failure results from neointimal hyperplasia. p1158/59 is a collagen‐derived matricryptin shown to facilitate tissue regeneration through targeted basement membrane protein deposition and vascularization. Accordingly, we hypothesized that p1158/59 SV treatment, prior to grafting, would modulate early vascular remodeling by modifying basal lamina composition and modulating intima growth, consistent with better graft patency.A canine model of carotid artery bypass was used. Animals (n=12; 25–35 kg) were anesthetized, intubated, and ventilated with 1–3% isoflurane, oxygen, and room air. A lateral hind limb incision was made and approximately 12–15 cm (in situ) of SV harvested. One half of the SV served as control (vehicle‐treated) and the other half was treated with p1158/59 (1 μM; 1.5 h). Vehicle‐ and p1158/59‐treated veins were anastomosed end‐to‐side into the right and left common carotid arteries respectively. Once graft patency was established, the native artery was divided, all surgical wounds repaired, and animals recovered. Ten days later, SV grafts were removed and tissue stored for gene and protein expression and histological assessments.Of the 12 SV vehicle grafts, 2 were thrombosed and 10 were patent; 6 of the patent grafts were heavily encapsulated. In the p1158/59‐treated group, 2 grafts were thrombosed with one continuing to show a weak pulse. Of the other 10 treated SV grafts, 4 were encapsulated; however, the level of adhesions was fewer as compared to the respective vehicle graft. There was no difference in lumen area between vehicle and p1158/59 groups (1.20×106±0.11×106 μm2 versus 1.33×106±0.12×106 μm2). Gene array revealed increased expression of the pro‐angiogenic factors EGF, HGF, and TGF‐β3 in the p1158/59 groups (all p<0.05 versus vehicle). Aminopeptidase N, known to regulate the biological activity of various peptides and to be highly expressed in macrophages with elevated phagocytic function, was also overexpressed in the p1158/59‐treated SV grafts when compared to vehicle (p<0.05). Histological analysis revealed similar expression of vascular elastin between groups but increased levels of collagen in the p1158/59‐treated group in the distal area of the graft when compared to vehicle (p<0.05).Our data suggest p1158/59 reduced graft encapsulation and adhesion formation after 10 days of SV engraftment and modulated vascular collagen remodeling.Support or Funding InformationWe acknowledge support from the American Heart Association 14SDG18860050