gms | German Medical Science

Objective: Bone marrow derived endothelial progenitor cells (EPC) contribute to adult blood vessel formation and may play a role in the increased collateral vessel growth seen in patients with coronary artery disease and chronic cerebral hypoperfusion. This might open the venue for future cellular therapies in chronic steno-occlusive disease. To this end, the purpose of this study was to investigate the effect of a specific EPC phenotype (late outgrowth endothelial colony forming cells, ECFC) on collateral remodeling and functional rescue in a mouse model of chronic cerebral hypoperfusion.

Method: CD34+ mononuclear cells were isolated from fresh human cord blood and cultured to derive ECFC. Human umbilical vein endothelial cells (HUVEC) served as control. Chronic cerebral hypoperfusion was simulated by unilateral external and internal carotid artery occlusion (E/ICAO) in NMRI nu/nu female mice aged 8-12 weeks. ECFC low dose (-LD) (3x105 cells), ECFC high dose (-HD) (1x10 cells), HUVEC (3x106 cells) or vehicle (phosphate buffered saline, PBS) were injected into the tail vein immediately after (day 0) and on days 3 and 7 after E/ICAO in 10-12 animals per group. Baseline perfusion and cerebrovascular reactivity (CVR) were assessed on days 0, 3, 7 and 14 by Laser Speckle Imaging. Basal and leptomeningeal collateral vessel growth was assessed on day 21 by latex/carbon black perfusion.

Results: On day 0, baseline perfusion or CVR did not differ between groups (Baseline perfusion / CVR: PBS 422.4±77Flux / 22.1±14%; HUVEC 423.6±90Flux / 31.1±11%; ECFC-LD 364±68Flux / 32.2±17%; ECFC-HD 375.3±69 Flux / 29.1±18%; p>0.05, two-way ANOVA for repeated measures). By day 14, baseline perfusion increased by 50% but only ECFC-HD (39.9±10%) and not ECFC-LD (32.7±15%) resulted in a significant functional recovery of CVR compared to HUVEC (22.2±18%; p=0.02) or PBS (24.2±20%; p=0.04). This dose-dependent effect of ECFC was associated with a significant increase of both the number (ECFC-HD 36.2±4*; ECFC-LD 28.8±2; HUVEC 28.3±4; PBS 30.9±4; *p<0.05 vs. other groups, one-way ANOVA) and diameter of leptomeningeal anastomoses after ECFC-HD. This effect coincided with less collateral outgrowth at the level of the basal vasculature.

Conclusions: ECFC have the potential to promote functional recovery and leptomeningeal remodeling in a dose-dependent manner. First evidence indicates that this effect seems to outweigh the benefit of collateral remodeling at the level of the basal vasculature.