Background and Purpose: The Bilateral carotid artery stenosis model in mice (BCAS) is regarded as a model for vascular cognitive impairment (VCI) and cerebral small vessel disease (SVD). We have shown that repetitive remote ischemic conditioning (RIC) increases cerebral blood flow (CBF), reduces white matter damage and improves cognition in the BCAS mouse model. The purpose of this study was to determine whether RIC increased angiogenesis and increased endothelial progenitor cells (EPC) in the blood or changed the polarization of macrophages in the blood.
Methods: Microcoil induced bilateral common carotid artery (BCAS) model was used to induce chronic hypoperfusion. Adult C57BL/6J male mice of (10-weeks) were randomized to 3-different groups (N=9), and subjected to Sham-(procedures of BCAS and RIC), BCAS+shamRIC and BCAS+RIC. RIC was started 7d post-surgery daily for 3 weeks. In all the experimental groups and after 3 weeks blood were collected through cardiac puncture and perfused with BriteVu. EPC (CD31, VEFR2, CD34) and M1/M2 macrophages were assessed through flow cytometry and angioarchitecture (vascular volume, number of vessels, linear spacing between vessels, density, average lumen thickness, and collateral circulation vessels) was performed with micro-CT scanner. All observers were blinded. Statistical significance was determined at p <0.05.
Results: RIC-therapy significantly improved CBF in the BCAS+RIC group compared to BCAS +shamRIC. EPCs were increased in the blood of the BCAS+RIC compared to BCAS+sham RIC and there was increased polarization (ratio of M2/M1) of macrophages in the blood in BCAS+RIC group compared to BCAS+shamRIC. RIC increased angiogenesis compared to sham RIC with increased vascular volume, number of vessels and decreased space between vessels.
Conclusions: Repetitive RIC increases angiogenesis and increases EPCs in the blood after BCAS. RIC also polarizes macrophages to the M2 (anti-inflammatory subset). Repetitive RIC may be an effective therapy to slow down the progression of VCI and SVD by promoting angiogenesis and vascular remodeling.