Erythropoietin-Mobilized Endothelial Progenitors Enhance Reendothelialization via Akt-Endothelial Nitric Oxide Synthase Activation and Prevent Neointimal Hyperplasia

Urao, Norifumi; Okigaki, Mitsuhiko; Yamada, Hiroyuki; Aadachi, Yasushi; Matsuno, Kuniharu; Matsui, Akihiro; Matsunaga, Shinsaku; Tateishi, Kento; Nomura, Tetsuya; Takahashi, Toshifumi; Tatsumi, Tomohide; Matsubara, Hiroaki

doi:10.1161/01.res.0000224117.59417.f3

Cited by 209 publications

(178 citation statements)

References 37 publications

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“…In accordance, EPO stimulated ischemia-induced angiogenesis and repair of injured arterial wall by mobilization of progenitor cells [5,12,25]. In the present study, we demonstrate that EPO stimulates mobilization of hematopoietic progenitor cells through an Enos-dependent mechanism even in the absence of ischemia.…”

Section: Discussionsupporting

confidence: 86%

Activation of endothelial nitric oxide synthase is critical for erythropoietin-induced mobilization of progenitor cells

et al. 2008

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The present study aimed to define the ability of erythropoietin (EPO) to mobilize hematopoietic stem cells (c-kit + /sca-1 + /lin-1 − ; KSL cells) and hematopoietic progenitor cells (CD34 + cells), including vascular endothelial growth factor receptor 2 expressing hematopoietic progenitor cells (CD34 + / Flk-1 + cells). We also sought to determine the role of endothelial nitric oxide synthase (eNOS) in EPO-induced mobilization. Wild type (WT) and eNOS −/− mice were injected biweekly with recombinant erythropoietin (EPO, 1000 U/kg, s.c.) for 14 days. EPO increased the number of KSL, CD34 + , CD34 + /Flk-1 + cells in circulating blood of wild type mice. These effects of EPO were abolished in eNOS −/− mice. Our results demonstrate that, EPO stimulates mobilization of hematopoietic stem and progenitor cells. This effect of EPO is critically dependent on activation of eNOS.

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Section: Discussionsupporting

confidence: 86%

Activation of endothelial nitric oxide synthase is critical for erythropoietin-induced mobilization of progenitor cells

et al. 2008

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“…For instance, shear stress, the major physiological stimulation in the vascular system, was found to activate AMPK, which in turn phosphorylated eNOS at Ser635 and Ser1179, thus leading to enhanced NO bioavailability (27,36). Additionally, several cytokines such as vascular endothelial growth factor and erythropoietin have been postulated to promote endothelial progenitor cell differentiation, EC survival and angiogenesis through an AMPK signaling pathway (37)(38)(39)(40)(41). In addition to the beneficial effects of AMPK in the endothelium, activation of AMPK by the pharmacological activator aminoimidazole-carboxamideribonucleotide (AICAR) profoundly inhibited platelet-derived growth factoror angiotensin II-induced smooth muscle cell proliferation (42).…”

Section: A M P K I N T R P V 1 -M E D I a T E D E N O S A C T I Vmentioning

confidence: 99%

Implication of AMP-Activated Protein Kinase in Transient Receptor Potential Vanilloid Type 1-Mediated Activation of Endothelial Nitric Oxide Synthase

Ching

Chen

et al. 2012

Mol Med

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We investigated whether AMP-activated protein kinase (AMPK), a multifunctional regulator of energy homeostasis, is involved in transient receptor potential vanilloid type 1 (TRPV1)-mediated activation of endothelial nitric oxide synthase (eNOS) in endothelial cells (ECs) and mice. In ECs, treatment with evodiamine, the activator of TRPV1, increased the phosphorylation of AMPK, acetyl-CoA carboxylase (ACC) and eNOS, as revealed by Western blot analysis. Inhibition of AMPK activation by compound C or dominant-negative AMPK mutant abrogated the evodiamine-induced increase in phosphorylation of AMPK and eNOS and NO bioavailability, as well as tube formation in ECs. Immunoprecipitation and two-hybrid analysis demonstrated that AMPK mediated the evodiamine-induced increase in the formation of a TRPV1-eNOS complex. Additionally, TRPV1 activation by evodiamine increased the phosphorylation of AMPK and eNOS in aortas of wild-type mice but did not activate eNOS in aortas of TRPV1-deficient mice. In mice, inhibition of AMPK activation by compound C markedly decreased evodiamine-evoked angiogenesis in matrigel plugs and in a hind-limb ischemia model. Moreover, evodiamine-induced phosphorylation of AMPK and eNOS in aortas of apolipoprotein E-deficient (ApoE -/-) mice was abrogated in TRPV1-deficient ApoE -/-mice. In conclusion, TRPV1 activation may trigger AMPK-dependent signaling, which leads to enhanced activation of AMPK and eNOS and retarded development of atherosclerosis.

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“…In mice, exogenous EPO mobilization of circulating endothelial progenitor cells promotes repair of injured endothelium with up regulation of EPO-R expression, phosphorylation of Akt and endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) synthesis on circulating endothelial progenitor cells [66,68]. During exposure to chronic hypoxia, endogenous EPO promotes recruitment of circulating endothelial progenitor cells preventing pulmonary hypertension in wild type mice, but not in mice lacking EPO-R in nonerythroid lineages resulting in acceleration of pulmonary hypertension and vascular remodeling [17].…”

Section: Epo Mobilization Of Endothelial Progenitor Cellsmentioning

confidence: 99%

“…During embryogenesis, deletion of EPO or EPO-R in mice results in angiogenic defects at midgestation with decreased complexity of vessel networks 3 days prior to embryonic death due to severe anemia [69]. EPO stimulation of endothelial progenitor cells is an important component of EPO activity in vascular injury [68], and may contribute to EPO protection of in other non-hematopoietic organ systems including the ischemic brain.…”

Section: Epo Mobilization Of Endothelial Progenitor Cellsmentioning

confidence: 99%

Role of erythropoietin in the brain

Noguchi

Asavaritikrai

Teng

et al. 2007

Critical Reviews in Oncology/Hematology

207

159

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Multi-tissue erythropoietin receptor (EPO-R) expression provides for erythropoietin (EPO) activity beyond its known regulation of red blood cell production. This review highlights the role of EPO and EPO-R in brain development and neuroprotection. EPO-R brain expression includes neural progenitor cells (NPC), neurons, glial cells and endothelial cells. EPO is produced in brain in a hypoxia sensitive manner, stimulates NPC proliferation and differentiation, and neuron survival, and contributes to ischemic preconditioning. Mice lacking EPO or EPO-R exhibit increased neural cell apoptosis during development before embryonic death due to severe anemia. EPO administration provides neural protection in animal models of brain ischemia and trauma, reducing the extent of injury and damage. EPO stimulation of endothelial cells contributes to neuroprotection and is of particular importance since only low levels of EPO appear to cross the blood-brain barrier when administered at high dose intravenously. The therapeutic potential of EPO for brain ischemia/trauma and neurodegenerative diseases has shown promise in early clinical trial and awaits further validation.

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Erythropoietin-Mobilized Endothelial Progenitors Enhance Reendothelialization via Akt-Endothelial Nitric Oxide Synthase Activation and Prevent Neointimal Hyperplasia

Cited by 209 publications

References 37 publications

Activation of endothelial nitric oxide synthase is critical for erythropoietin-induced mobilization of progenitor cells

Activation of endothelial nitric oxide synthase is critical for erythropoietin-induced mobilization of progenitor cells

Implication of AMP-Activated Protein Kinase in Transient Receptor Potential Vanilloid Type 1-Mediated Activation of Endothelial Nitric Oxide Synthase

Role of erythropoietin in the brain

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