Accelerated Arteriogenesis In Collateral Arterial Segments Exposed To Flow Reversal After Femoral Arterial Ligation

Abstract

Elevated fluid shear stress is known to be a key stimulus for driving arteriogenesis; however, the role that flow‐reversal (FR) plays in arteriogenesis is largely unknown. We hypothesized that FR in spatially distinct regions of collateral arteries (CAs) can lead to spatially distinct variations in CA growth.METHODSUnilateral femoral artery ligation (FAL) was performed in C57Bl6 mice. Gracilis muscles were harvested at 1, 7, 14, and 28 days after FAL and immunolabeled for smooth muscle α‐actin to visualize CAs. As determined by intravital microscopy, FAL increased flow across the length of the primary gracilis CAs with distinct regions of flow reversal (FR) and non‐flow reversal (NFR).RESULTSBoth FR and NFR CA segments showed significant growth as compared to the unligated (control) leg arterial diameters at days 7, 14, and 28 (p<0.001). However, CA regions experiencing FR showed significantly greater expansion of lumenal diameter (arteriogenesis) compared to the NFR regions at days 7 and 14 (p<0.005). This increase became non‐significant by day 28. At day 7, CD45+ leukocyte density was significantly greater around FR CA segments as compared to NFR segments (6.3±3.9 versus 3.9±2.1 CD45+ cells/collaterals, p<0.05, respectively). Further, pericollateral CD45+ cell density significantly correlated with CA diameter in ligated (R2=0.41, p<0.05), but not in unligated CAs (R2=0.0024, p=0.64).CONCLUSIONSThese data suggest that there are spatial variations in CA growth, CD45+ cell recruitment, and changes in hemodynamics along the length of a given CA after FAL. Together, our data suggest differences in mechanotransduction along a CA lead to differentialgrowth, with increased leukocyte accumulation as a potential mechanism. Supported by NIH HL074082, NIH R21HL098632, AHA 09PRE2060385, AHA 10GRNT3490001.