ABSTRACT
BACKGROUND Aging plays an important role in endothelial dysfunction. Fluid shear stress (FSS) can activate endothelial cells (ECs). Herein, we tested the hypothesis that this endothelial impairment could be improved by elevated FSS (EFSS) in aged rats. MATERIAL AND METHODS EFSS was created through ligation of the unilateral common iliac artery in 20-month-old rats, evaluated by measuring blood flow velocity with Doppler spectrum. The effect of FSS on aged ECs was examined by senescence-associated ß-galactosidase (SA-ß-Gal) staining, ultrastructural observation, and immunostaining and qPCR analysis of eNOS and SIRT1 expression on both the mRNA and protein levels. RESULTS (1) FSS was significantly increased in the right common iliac artery (RCIA) in rats with the ligation of the left common iliac artery (LCIA). (2) SA-ß-Gal staining was significantly attenuated by EFSS in the RCIA of aged rats. (3) Ultrastructural observation showed that ECs in the RCIA of normal aged rats became irregular and enlarged, with increasingly polypoid nuclei and fewer mitochondria, whereas ECs in the RCIA of aged rats with LCIA ligation became more prominent and contained more mitochondria. (4) eNOS and SIRT1 expression in the RCIA of aged rats with LCIA ligation was significantly upregulated compared with that in control group rats. CONCLUSIONS The present study for the first time shows that EFSS has the ability to improve age-related impairment of endothelial structure and functions.
Subject(s)
Endothelium/pathology , Iliac Artery/pathology , Age Factors , Animals , Blood Flow Velocity , China , Endothelial Cells/metabolism , Endothelium, Vascular/metabolism , Hydrodynamics , Male , Nitric Oxide Synthase Type III/analysis , Nitric Oxide Synthase Type III/metabolism , Rats , Rats, Sprague-Dawley , Sirtuin 1/analysis , Sirtuin 1/metabolism , Stress, Mechanical , Structure-Activity Relationship , Vascular DiseasesABSTRACT
Although collateral vessel growth is distinctly enhanced by elevated fluid shear stress (FSS), the underlying regulatory mechanism of this process remains incompletely understood. Recent studies have shown that microRNAs (miRNAs) play a pivotal role in vascular development, homeostasis and a variety of diseases. Therefore, this study was designed to identify miRNAs involved in elevated FSS-induced collateral vessel growth in rat hind limbs. A side-to-side arteriovenous (AV) shunt was created between the distal stump of one of the bilaterally occluded femoral arteries and the accompanying vein. The miRNA array profile showed 94 differentially expressed miRNAs in FSS-stressed collaterals including miRNA-352 which was down-regulated. Infusion of antagomir-352 increased the number and proliferation of collateral vessels and promoted collateral flow restoration in a model of rat hind limb ligation. In cell culture studies, the miR-352 inhibitor increased endothelial proliferation, migration and tube formation. In addition, antagomir-352 up-regulated the expression of insulin-like growth factor II receptor (IGF2R), which may play a part in the complex pathway leading to arterial growth. We conclude that enhanced collateral vessel growth is controlled by miRNAs, among which miR-352 is a novel candidate that negatively regulates arteriogenesis, meriting additional studies to unravel the pathways leading to improved collateral circulation.
