Human Erythropoietin Induces a Pro-Angiogenic Phenotype in Cultured Endothelial Cells and Stimulates Neovascularization In Vivo

Ribatti, Doménico; Presta, Marco; Vacca, Angelo; Ria, Roberto; Giuliani, Roberta; Dell’Era, Patrizia; Nico, Beatrice; Roncali, Luisa; Dammacco, Franco

doi:10.1182/blood.v93.8.2627

Cited by 475 publications

(181 citation statements)

References 54 publications

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“…Erythropoietin binding to its receptor in differentiating haematopoietic cells activates JAK/STAT and other signal transduction pathways to control cellular proliferation, survival and specific gene expression. Accordingly, endothelial cells expressed EpoR that bound JAK2 and included its transient activation after rHuEpo exposure [29]. It is interesting to note that JAK2 is involved in the intracellular signalling of receptors for various cytokines, including the angiogenic G-CSF and GM-CSF [30].…”

Section: Erythropoietin and Angiogenesismentioning

confidence: 99%

“…Recombinant human Epo induces a proangiogenic phenotype in human endothelial cells, including both early (i.e. increase in cell proliferation and matrix metalloproteinase-2 production) and late (differentiation into vascular tubes) angiogenic events [29]. In vivo , in the chick embryo CAM assay, the angiogenic activity of rHuEpo was similar to that exerted by FGF-2, a well-known angiogenic cytokine, and endothelial cells of the CAM expressed EpoR, which colocalized with factor VIII positivity [29].…”

Section: Erythropoietin and Angiogenesismentioning

confidence: 99%

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Erythropoietin as an angiogenic factor

Ribatti

Vacca

Roccaro

et al. 2003

Eur J Clin Investigation

146

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Erythropoietin (Epo) is produced by the fetal liver and adult kidney and is an essential stimulator of erythropoiesis. It has, however, been shown to modulate host cellular signal transduction pathway to perform many other functions. New sites of Epo production have been found, such as the female reproductive organs and central nervous system. This review summarizes the involvement of Epo in the regulation of angiogenesis in both normal and pathological conditions.

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Section: Erythropoietin and Angiogenesismentioning

confidence: 99%

Section: Erythropoietin and Angiogenesismentioning

confidence: 99%

Erythropoietin as an angiogenic factor

Ribatti

Vacca

Roccaro

et al. 2003

Eur J Clin Investigation

146

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“…EPO-R mRNA and EPO binding sites have been demonstrated in a variety of organs, including the heart, blood vessels, kidneys, liver, gastrointestinal tissues, pancreatic islands, testis, female reproductive tract, placenta and, as a separate entity, the brain (Sasaki et al, 2000). EPO mobilizes endothelial progenitor cells and promotes neovascularization (Ribatti et al, 1999;Heeschen et al, 2003). Recent studies in ischaemia/reperfusion animal models of cardiac infarct have shown that EPO reduces the infarct area size, improves recovery of mechanical function and increases coronary flow, partly by exerting anti-apoptotic effects on cardiomyocytes and partly by preventing endothelial cell apoptosis (for review see Schwartzenberg et al, 2006).…”

Section: Epo As a Pleiotropic Cytoprotectantmentioning

confidence: 99%

Developments in the therapeutic use of erythropoiesis stimulating agents

Jelkmann¹

2008

Br J Haematol

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SummaryRecombinant human erythropoietin (rHuEPO) has become the standard therapy for treatment of the anaemia of chronic kidney disease (CKD) during the past two decades. In addition, rHuEPO can be indicated for the treatment of cancer patients on chemotherapy and surgical patients to avoid allogeneic red blood cell transfusion. This review first describes recent attempts in developing rHuEPO congeners (mutated and pegylated rHuEPOs) and mimetics with prolonged halflives and improved application requirements. Secondly, the pathophysiological background of the regulatory guideline, that blood haemoglobin levels in anaemic CKD or cancer patients on chemotherapy should not be raised above the target value of 120 g/l, is discussed. Finally, potential novel indications are considered for the use of rHuEPO and its analogues as pleiotropic cytoprotectant agents for cardio-, nephro-, hepato-and neuroprotection.Keywords: anaemia, erythropoiesis stimulating agents, erythropoietin, haemoglobin, tissue protection.The glycoprotein hormone erythropoietin (EPO) is an essential survival and growth factor for the erythrocytic progenitors in bone marrow and other haemopoietic tissues. EPO prevents the apoptotic cell death of erythroid colonyforming units (CFU-Es), promotes their proliferation and differentiation to yield a herd of pro-normoblasts, and accelerates the development of reticulocytes by shortening the transition time through the pro-normoblast and normoblast stages. As it takes several days for the CFU-Es to produce the progeny of reticulocytes, a significant increase in haematocrit (Hct) is usually not observed earlier than about 2 weeks after a rise in the plasma EPO concentration. Lack of EPO results in anaemia.The kidneys are the main sites for the production of EPO in adult humans. Here, and in other EPO producing organs, such as the liver, the rate of the expression of the EPO gene depends on the level of tissue oxygenation through the availability of the hypoxia-inducible transcription factor 2 (HIF-2). The plasma EPO level can increase up to three orders of magnitude above the normal value of about 0AE015 units/ml (U/ml) in anaemia or hypoxaemia. This response is missing in patients with the anaemia of chronic kidney disease (CKD). The aetiology of the anaemia of inflammation and cancer is more multifactorial, as it involves a relative lack of EPO, insufficient iron availability as a result of the blocking action of hepcidin, inhibition of the proliferation of the erythrocytic progenitors by cytokines, shortened red blood cell (RBC) survival and, possibly, bleeding.Following the cloning of the human EPO gene (EPO) and its in vitro expression, recombinant human EPO (rHuEPO) was initially licensed for the treatment of predialysis and dialysis CKD patients and, more recently, cancer patients receiving chemotherapy for solid tumours, malignant lymphomas or multiple myelomas. The therapy with rHuEPO and its analogues aims at avoiding the need for RBC transfusion. Other indications for the administration of erythrop...

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“…Interestingly, studies have demonstrated that beside this effect on erythropoiesis, EPO also promotes angiogenesis (Anagnostou, Lee, Kessimian, Levinson, & Steiner, 1990). For instance, Ribatti et al (1999) found T A B L E 2 Diameter (μm), centreline RBC velocity (μmÁs −1 ), and volumetric blood flow (plÁs −1 ) of newly formed microvessels within islets on Days 3, 6, 10, and 14 after transplantation into the dorsal skinfold chamber of FVB/N mice, which were pretreated with vehicle (ctrl-pre, n = 8) or EPO (EPO-pre, n = 8)…”

Section: Discussionmentioning

confidence: 99%

Erythropoietin accelerates the revascularization of transplanted pancreatic islets

Menger

Nalbach

Roma

et al. 2020

British J Pharmacology

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Background and Purpose Pancreatic islet transplantation is a promising therapeutic approach for Type 1 diabetes. A major prerequisite for the survival of grafted islets is a rapid revascularization after transplantation. Erythropoietin (EPO), the primary regulator of erythropoiesis, has been shown to promote angiogenesis. Therefore, we investigated in this study whether EPO improves the revascularization of transplanted islets. Experimental Approach Islets from FVB/N mice were transplanted into dorsal skinfold chambers of recipient animals, which were daily treated with an intraperitoneal injection of EPO (500 IU·kg−1) or vehicle (control) throughout an observation period of 14 days. In a second set of experiments, animals were only pretreated with EPO over a 6‐day period prior to islet transplantation. The revascularization of the grafts was assessed by repetitive intravital fluorescence microscopy and immunohistochemistry. In addition, a streptozotocin‐induced diabetic mouse model was used to study the effect of EPO‐pretreatment on the endocrine function of the grafts. Key Results EPO treatment slightly accelerated the revascularization of the islet grafts. This effect was markedly more pronounced in EPO‐pretreated animals, resulting in significantly higher numbers of engrafted islets and an improved perfusion of endocrine tissue without affecting systemic haematocrit levels when compared with controls. Moreover, EPO‐pretreatment significantly accelerated the recovery of normoglycaemia in diabetic mice after islet transplantation. Conclusion and Implications These findings demonstrate that, particularly, short‐term EPO‐pretreatment represents a promising therapeutic approach to improve the outcome of islet transplantation, without an increased risk of thromboembolic events.

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Human Erythropoietin Induces a Pro-Angiogenic Phenotype in Cultured Endothelial Cells and Stimulates Neovascularization In Vivo

Cited by 475 publications

References 54 publications

Erythropoietin as an angiogenic factor

Erythropoietin as an angiogenic factor

Developments in the therapeutic use of erythropoiesis stimulating agents

Erythropoietin accelerates the revascularization of transplanted pancreatic islets

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