Comment on Hristov et al, page 2761
Endothelial-derived apoptotic bodies are ingested by endothelial progenitor cells, resulting in these cells' enhanced proliferation and differentiation. This mechanism may contribute to the repair and maintenance of the vascular endothelium.
The endothelium maintains blood-organ barriers, regulates vasomotor tone, and prevents thrombosis, among other functions. A healthy endothelium is among the most stable tissues, with a turnover time estimated at more than 1000 days. During vascular trauma, angiogenesis, wound healing, and ovulation, however, the turnover rate of the microvascular endothelium may increase dramatically, approaching that of bone marrow cells.1 If the repair of dysfunctional, eroded, or apoptotic endothelium is inadequate, diseases such atherosclerosis and its ischemic sequelae may ensue.
Despite the clear importance of a healthy endothelium, the mechanisms by which it is repaired are not fully understood. A traditional view has been that arterial injury induces the expression of survival genes and mitogens such as vascular endothelial growth factor that act in a paracine fashion to induce neighboring endothelial cells to proliferate, migrate, and repopulate the damaged surfaces. The discovery of circulating bone marrow-derived endothelial progenitor cells (EPCs)2 has provided an alternative mechanism in which EPCs contribute to vascular growth and repair in a process that is analogous to vasculo-genesis. However, the details by which EPCs are recruited from the bone marrow and home to, proliferate, and differentiate at the specific sites of vascular injury remain obscure.
In this issue, Hristov and colleagues provide intriguing insights into some of these events. EPCs were found to phagocytose apoptotic bodies from endothelial and HL-60 cells. Of most interest was the observation that endothelial-derived (but not HL-60-derived) apoptotic bodies increased the rates of proliferation and differentiation of the EPCs. Additional research is needed to determine the active components of the apoptotic bodies. A reasonable candidate is DNA but other possibilities include sequestered growth factors or membrane-bound receptors. If this effect is confirmed by additional studies, it would represent a significant step forward in EPC biology.
There are several important implications of these findings. Harvested EPCs could be amplified by culturing them in the presence of apoptotic bodies. As the authors note, the up-take of apoptotic bodies by EPCs could be exploited as a novel strategy for molecular therapy. This same phenomenon could also be manipulated to enhance endothelial cell repair or to inhibit angiogenesis in vivo. Patients who have coronary artery disease or risk factors including advanced age3 and smoking4 have reduced numbers of circulating EPCs. Dysfunctional adhesion, migration, and proliferation of EPCs have been described in diabetic patients.5 A failure of EPCs to ingest or to mount a robust proliferative response to endothelial-derived apoptotic bodies could contribute to EPC depletion in conditions that predispose to atherosclerosis. On the flip side, tumor angiogenesis could potentially be abrogated by disrupting these same events.
It appears that the endothelium has a life insurance plan. Understanding the details will produce the maximum long-term benefit for vascular health.