Erythropoietin: when liability becomes asset in neurovascular repair

Abstract

Erythropoietin (Epo) leads to the proliferation and differentiation of erythroid precursors, but is also involved in diverse nonhematopoietic biological functions. In this issue of the JCI, Chen, Smith, and colleagues demonstrate that the temporal expression of Epo is critical for determining whether physiological or pathological repair occurs following neurovascular retinal injury in the oxygen-induced retinopathy neonatal mouse model (see the related article beginning on page 526). The pleiotrophic properties of Epo make it a likely novel therapy for treatment of neurovascular damage, but the timing of its use must be carefully considered to prevent untoward effects.

Figure 1. Mouse model of proliferative OIR.

In this model, 7-day-old mouse pups with partially developed retinal vasculature are subjected for 5 days to hyperoxia (75% oxygen), which stops retinal vessel growth and causes significant vaso-obliteration (phase 1). On postnatal day 12, pups are returned to room air, and by postnatal day 17, a florid compensatory retinal neovascularization occurs (shown in white) (phase 2). In the line graph, a representation of retinal Epo mRNA levels in the OIR model during normoxic conditions (green), phase 1 (red), and phase 2 (blue) are shown. As Chen et al. (5) show, in the OIR model during hyperoxia (phase 1), Epo levels are reduced, resulting in pathological elevations of Epo at the late stage of disease development. With Epo treatment during hyperoxia, retinal vasculature is protected and BM-derived EPCs come into the developing vasculature, promoting healthy vessels rather than pathological neovascularization as in the OIR model. Original magnification, ×5.

Figure 2. Epo’s angiogenic effects.

Epo has direct effects on resident vasculature, and it mobilizes circulating CD34⁺ BM-derived populations to stimulate their contribution to vascular repair in both acute and chronic injury models. BM-derived EPCs circulate in the bloodstream and migrate to areas of ischemia, respond to hypoxia-regulated factors such as Epo, and participate in both physiological and pathological neovascularization. Epo stimulates EPC proliferation, adhesion, and differentiation to endothelium, as do other hypoxia-regulated factors such as VEGF, stromal cell–derived factor 1 (SDF-1), and insulin-like growth factor–binding protein 3 (IGFBP-3).