Time Changes in the VEGF-A Concentration Gradient Lead Neovasculature to Engage in Stair-Like Growth

Abstract

Arteriovenous malformations consist of tangles of arteries and veins that are often connected by a fistula. The causes of and mechanisms underlying the development of these clinical entities are not fully understood. We previously reported a novel in vivo angiogenesis model as a useful disease model of arteriovenous malformation. With this model, the arterial graft was collected from the left carotid artery and sutured to the left jugular vein as a patchwork. The neovasculature extended from the branch of the subclavian artery toward the arterial graft. We measured the neovasculature, which had sprouted from arterioles, in the tissue samples. In the present study, we collected the arterial patch graft and adipose tissue surrounding the arterial graft and examined the distribution of the VEGF concentration by an enzyme-linked immunosorbent assay. At the area most distant from the arterial graft, the VEGF-A concentration changed over time in a sine wave pattern that gradually attenuated. A mathematical model was then constructed using the results, and a mathematical simulation of the neovasculature growth was performed. The new vessels grew in a stair-like pattern in this simulation, a result that matched those obtained through histological measurements.