Induction of extracranial arteriogenesis by an arteriovenous fistula in a pig model.

BACKGROUND AND AIMS: Arteriogenesis, the positive outward remodeling and growth of pre-existent collateral vessels, holds potential as a novel treatment for ischemic vascular disease. An extracranial arteriogenesis model in a pig will allow us to study molecular changes in a complex arteriolar network in a more clinically relevant large-animal model. To increase fluid shear stress in the brain, an experimental carotid arteriovenous fistula (AVF model) in minipigs was established, providing high flow through the extracranial rete mirabile. The aim of the study was to examine whether creation of a carotid AVF can induce extracranial arteriogenesis in the pig. METHODS: Angiography was performed to demonstrate blood flow diversion. Animals were sacrificed after 0, 3 and 14 days post-surgery and both retia mirabilia were removed. Immunohistochemical analysis was performed to analyze cell proliferation and accumulation of mononuclear cells in the vessel wall. RESULTS: After 3 days of high-flow conditions, increases in vascular cell proliferation (approximately 1.5-fold; p = 0.143) and monocyte invasion (approximately 6-fold; p = 0.057) were observed when compared to animals sacrificed immediately after AVF formation. Quantitative PCR (RT-qPCR) analysis from rete mirabile tissue samples 3 days post-surgery revealed that monocyte chemoattractant protein (MCP)-1 and tissue inhibitor of metalloproteinases (TIMP)-1 were highly upregulated. Expression of the pro-arteriogenic marker, CD44, reached maximum expression level 14 days post-surgery. CONCLUSIONS: In response to high levels of shear stress produced in the pig AVF model, the onset of the arteriogenic process can be induced. This was demonstrated by enhanced cell proliferation, monocyte invasion and vascular remodeling.