Molecular insight into angiogenesis
CLI is characterised by inadequate tissue vascularisation and most efforts have focused on strategies that promote angiogenesis. Accumulating data suggest the clinical potential of vascular progenitor cells (PCs) to restore blood flow to the ischaemic limb. PCs are mobilised from the bone marrow and recruited to the site of ischaemia, where they participate in functional repair. However, most studies have failed to show long-term benefit, indicating the requirement of novel factors that drive PC mobilisation and homing to the ischaemic tissue. Towards this goal, scientists on the EU-funded CAPI (Role of cyclophilin A in bone marrow vascular progenitor cell mobilization and recruitment in the angiogenic response to ischemia) project focused on the interaction of stromal-derived factor 1 (SDF-1) with the CXCR4 receptor in angiogenesis. Of particular interest was the mediator cyclophilin A (CyPA), which binds to CXCR4 and modulates SDF-1-mediated chemotactic cell migration. To delineate the role of CyPA in PC biology, scientists treated bone marrow-derived PCs with different concentrations of CyPA and found a dose-dependent impact on PC migration. Also, the absence of CyPA on PCs led to a significantly reduced migration capacity in response to SDF-1 compared to wild-type controls. Results from mice with acute hind-limb ischaemia (HLI) demonstrated an increased mobilisation of PCs from the bone marrow to the peripheral circulation after CyPA treatment. At the same time, administration of the CXCR4 antagonist AMD3100 decreased PC mobilisation underscoring the importance of the SDF-1–CXCR4 axis in CyPA-mediated angiogenesis. Mechanistic insight into the process revealed that CyPA increased SDF-1 serum levels and up-regulated CXCR4 expression on PCs. This resulted in an increased PC recruitment to the ischaemic limb. Furthermore, CyPA improved post-injury neovascularisation by increasing limb perfusion, capillary density, and arteriole length density. Altogether, the findings of the CAPI study demonstrate that CyPA might serve as a useful therapeutic strategy for accelerating angiogenesis in ischaemic cardiovascular diseases such as CLI. Considering that patients with advanced disease are usually unsuitable for revascularisation procedures, CyPA treatment could provide an alternative solution.
Keywords
Angiogenesis, critical limb ischaemia, vascular progenitor cells, bone marrow, SDF-1, CXCR4, cyclophilin A