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Erythropoietin: when liability becomes asset in neurovascular repair
Maria B. Grant,1 Michael E. Boulton,2 and Alexander V. Ljubimov3
1Program in Stem Cell Biology and Regenerative Medicine, Department of Pharmacology and Therapeutics, University of Florida, Gainesville, Florida, USA. 2Age-Related Macular Degeneration Center, Department of Ophthalmology and Visual Sciences, University of Texas Medical Branch, Galveston, Texas, USA. 3Ophthalmology Research Laboratories, Cedars-Sinai Medical Center, and UCLA David Geffen School of Medicine, Los Angeles, California, USA.
Address correspondence to: Maria B. Grant, Department of Pharmacology and Therapeutics, University of Florida, Box 100267, Gainesville, Florida 32610, USA. Phone: (352) 846-0978; Fax: (352) 392-9696; E-mail: grantma@ufl.edu.
Find articles by Grant, M. in: JCI | PubMed | Google Scholar
1Program in Stem Cell Biology and Regenerative Medicine, Department of Pharmacology and Therapeutics, University of Florida, Gainesville, Florida, USA. 2Age-Related Macular Degeneration Center, Department of Ophthalmology and Visual Sciences, University of Texas Medical Branch, Galveston, Texas, USA. 3Ophthalmology Research Laboratories, Cedars-Sinai Medical Center, and UCLA David Geffen School of Medicine, Los Angeles, California, USA.
Address correspondence to: Maria B. Grant, Department of Pharmacology and Therapeutics, University of Florida, Box 100267, Gainesville, Florida 32610, USA. Phone: (352) 846-0978; Fax: (352) 392-9696; E-mail: grantma@ufl.edu.
Find articles by Boulton, M. in: JCI | PubMed | Google Scholar
1Program in Stem Cell Biology and Regenerative Medicine, Department of Pharmacology and Therapeutics, University of Florida, Gainesville, Florida, USA. 2Age-Related Macular Degeneration Center, Department of Ophthalmology and Visual Sciences, University of Texas Medical Branch, Galveston, Texas, USA. 3Ophthalmology Research Laboratories, Cedars-Sinai Medical Center, and UCLA David Geffen School of Medicine, Los Angeles, California, USA.
Address correspondence to: Maria B. Grant, Department of Pharmacology and Therapeutics, University of Florida, Box 100267, Gainesville, Florida 32610, USA. Phone: (352) 846-0978; Fax: (352) 392-9696; E-mail: grantma@ufl.edu.
Find articles by Ljubimov, A. in: JCI | PubMed | Google Scholar
Published January 24, 2008 - More info
J Clin Invest. 2008;118(2):467–470. https://doi.org/10.1172/JCI34643.
© 2008 The American Society for Clinical Investigation
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Abstract
Erythropoietin (Epo), a hormone known to stimulate bone marrow erythrocyte production, is widely used to treat anemia in patients at risk for vascular disease. However, the effects of Epo on angiogenesis are not well defined. We studied the role of Epo in a mouse model of retinopathy characterized by oxygen-induced vascular loss followed by hypoxia-induced pathological neovascularization. Without treatment, local retinal Epo levels were suppressed during the vessel loss phase. Administration of exogenous Epo prevented both vessel dropout and subsequent hypoxia-induced neovascularization. Early use of Epo also protected against hypoxia-induced retinal neuron apoptosis. In contrast, retinal Epo mRNA levels were highly elevated during the retinopathy neovascular phase. Exogenous late Epo treatment did not protect the retina, but rather enhanced pathological neovascularization. Epo’s early protective effect occurred through both systemic retinal recruitment of proangiogenic bone marrow–derived progenitor cells and activation of prosurvival NF-κB via Epo receptor activation on retinal vessels and neurons. Thus early retinal Epo suppression contributed to retinal vascular instability, and elevated Epo levels during the proliferation stage contributed to neovascularization and disease. Understanding the role of Epo in angiogenesis is critical to timing its intervention in patients with retinopathy or other diseases in which pathological angiogenesis plays a significant role.
Authors
Jing Chen, Kip M. Connor, Christopher M. Aderman, Lois E.H. Smith
In 1994, Smith and coworkers (1) developed and refined a neonatal mouse model of proliferative oxygen-induced retinopathy (OIR; Figure 1). In this model, 7-day-old mouse pups with partially developed retinal vasculature are subjected to hyperoxia (75% oxygen) for 5 days, which stops retinal vessel growth and causes significant vaso-obliteration. On postnatal day 12, the pups are returned to room air, and by postnatal day 17, a florid compensatory retinal neovascularization occurs. This model of pathological neovascularization has been widely used as a substitute for proliferative diabetic retinopathy (DR) and in studies of various antiangiogenic compounds (2–4).
Figure 1Mouse 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.
In this issue of the JCI, Chen, Smith, and associates highlight the importance of temporal expression of the hormone erythropoietin (Epo) in the pathogenesis of retinopathy using the OIR model (5). They report that during the hyperoxic phase of the OIR model, mRNA levels of retinal Epo were suppressed, while during the subsequent hypoxic phase Epo mRNA levels were greatly increased (Figure 1). Early administration of Epo protected against hyperoxia-induced retinal vaso-obliteration and neural apoptosis, preventing vessel dropout and hypoxia-induced neovascularization in the second phase of this disease model. However, treatment with exogenous Epo during the second phase of the OIR model actually increased pathological neovascularization. Furthermore, Chen et al. (5) also show that hyperoxia resulted in the loss of bone marrow–derived (BM-derived) endothelial progenitor cell (EPC) contribution to vascular development (2). During retinal development, the suppression of endogenous growth factors by hyperoxia with subsequent vaso-obliteration is the critical initiating event responsible for the development of pathological neovascularization. This aberrant neovascularization is responsible for the vision-threatening aspects of retinopathy of prematurity (ROP) and is also seen in DR (6, 7). Patients with these conditions are treated once pathological vessels appear. However, treating “late-stage” disease may be much less effective and, as shown in the current study by Chen et al. (5), early treatment may be a more judicious approach, at least in the case of Epo.
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Epo as a vasculogenic, neuroprotective, and EPC recruitment factor
The recent identification of critical hypoxia-regulated factors and the temporal changes in their expression represents an important step toward understanding mechanisms of disease progression in retinal neovascularization. The pharmaceutical industry has aggressively identified agents to specifically target late events in disease development when neovascularization is already present and to inhibit the hypoxia-regulated factors implicated in pathological neovascularization (8, 9). Most of these factors have intrinsic neural and retinal vascular protective effects, and their elimination may eventually contribute to cell and tissue dysfunction. More importantly, their expression represents a physiological adaptive response to ischemic tissue injury.
One such factor, Epo, is a glycoprotein (molecular mass is approximately 30 kDa) produced primarily in the kidney but with localized production also reported in a range of neural and nonneural tissues (10, 11). Epo is directly activated by the transcription factors HIF-1α (12), HIF-1α–like factor (HLF, also known as EPAS1) (13), and HIF-2α (14) and thus is induced in direct response to ischemic or hypoxic conditions. The Epo receptor (EpoR) also appears to be widely expressed, and ligand binding is associated with activation of the protein tyrosine kinase JAK2 and the downstream signaling molecule STAT5 (15, 16). EpoR can also signal through PI3K-Akt, MAPK, and, as shown in the current study by Chen et al., NF-κB (5). With this broad expression of both Epo and EpoR, a pleiotrophic role for Epo is anticipated. Whereas Epo is best known for its role in hematopoiesis as a factor that leads to the proliferation and differentiation of erythroid precursors, it is also involved in diverse nonhematopoietic biological functions (10, 17, 18). These pleiotrophic effects of Epo include: (a) neuroprotection by decreasing neuronal apoptosis and inflammation in acute brain injury models, by protecting the mouse retina against light-induced degeneration (19) and by reducing retinal ganglion cell loss following axotomy (20); (b) cytoprotection by inhibiting apoptosis and promoting angiogenesis to improve cardiac function in cardiac ischemia models of heart failure (21, 22); and (c) modulation of tissue remodeling by regulating cell maturation and division, preventing intimal hyperplasia (23), and reducing pulmonary vascular remodeling (24) in a hypoxic rat model of pulmonary hypertension without affecting hemodynamics or right ventricular hypertrophy.
Epo clearly has direct effects on resident vasculature and is known to mobilize circulating BM-derived cell populations to mediate vascular repair in both acute and chronic injury models (25, 26). BM-derived EPCs circulate in the bloodstream and are capable of endothelial repair. They migrate to areas of ischemia, respond to hypoxia-regulated factors such as Epo, and participate in both physiological and pathological neovascularization (Figure 2). Epo stimulates EPC proliferation, adhesion, and differentiation to endothelium.
Figure 2Epo’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).
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