Preconditioning of arteriogenesis

Abstract

OBJECTIVE: Last decade, the shear stress caused by increased blood flow in collateral circulation after occlusion of main artery was recognized as a trigger of vascular remodeling and collateral growth. The goal of this study was to differentiate whether the on-going increased blood flow is necessary for the vascular remodeling or the remodeling, once in progress, develops independently of flow. METHODS: Femoral artery occlusion was performed in C57B1/6 mice. After 1-3 days, the ligature was removed and normal limb perfusion was re-established, monitored by laser Doppler Imaging (LDI). Two weeks after the first occlusion, both femoral arteries were re-occluded to compare collateral growth on the "naive" and "preconditioned" sides. After perfusion fixation, ultrastructural studies and morphometry of the collateral vessels were performed. RESULTS: Blood flow fell after occlusion to about 15% of control levels and recovered to about 40% by day 3. The reperfusion normalized sustainable blood flow. After the second occlusion, blood flow on both sides fell again to about 15% but recovered to 70% in the "preconditioned" compared to 40% in the "naive" side during the following 3 days. 5-Bromo-2'-desoxy-uridine (BrdU) administered during reperfusion was detected mainly in the neointima that, in many cases, had markedly narrowed the lumen. Two to three days after re-occlusion, a statistically significant lumen enlargement on the "preconditioned" side was observed, while neointima disappeared. CONCLUSION: Cellular proliferation and remodeling of collateral arteries were induced by short period of increased blood flow (occlusion of the femoral artery) but realized mostly during the low blood flow (reperfusion of the femoral artery). The neointima developing as a result of this remodeling can be recruited as a functional part of the arterial wall if the collateral perfusion increases as a result of repetitive occlusion of the femoral artery. The "medialization" of the neointima might cause the observed quicker gain of collateral lumen diameter and conductance, saving distal muscle tissue from the ischemia.