Recombinant human erythropoietin augments angiogenic responses in a neonatal rat model of cerebral unilateral hypoxia-ischemia

Neonatology. 2014;106(2):143-8. doi: 10.1159/000362262. Epub 2014 Jun 24.


Background: Recombinant human erythropoietin (rh-EPO) has been used as a drug to treat premature infant anemia for over a decade. In addition to its erythropoietic effect, rh-EPO has also been reported to have protective effects against brain injury.

Objectives: Our aim was to evaluate the levels of angiogenesis-related cells (CD34+ cells) and angiogenic factors (vascular endothelial growth factor, VEGF, and angiopoietin-1, Ang-1) in a neonatal rat model of cerebral unilateral hypoxia-ischemia (HI) and to identify the effects of rh-EPO on angiogenic responses.

Methods: Postnatal day 3 (PD3) rats underwent permanent ligation of the right common carotid artery followed by 6% O2 for 4 h (HI) or sham operation and normoxic exposure (sham). Immediately after HI, the rats received a single intraperitoneal injection of rh-EPO (5 U/g) or saline. Angiogenesis-related cells (CD34+ cells) and angiogenic factors (VEGF and Ang-1) were examined on PD5, 7, 10 and 14.

Results: Compared with the sham rats, the number of CD34+ cells in HI rats increased from PD5 to 7 but decreased from PD10 to 14. VEGF and Ang-1 mRNA levels both increased from PD5 to 14. CD34+ cells, VEGF and Ang-1 were all upregulated in rh-EPO-treated rats compared with HI rats.

Conclusions: In the present study, we show the angiogenic effects of rh-EPO in a rat model of neonatal cerebral unilateral HI. Our results highlight the powerful therapeutic potential of rh-EPO treatment of HI premature brain for the enhancement of angiogenic responses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inducing Agents / pharmacology*
  • Angiopoietin-1 / genetics
  • Angiopoietin-1 / metabolism
  • Animals
  • Animals, Newborn
  • Antigens, CD34 / metabolism
  • Brain / blood supply*
  • Brain / drug effects*
  • Brain / metabolism
  • Brain / physiopathology
  • Cytoprotection
  • Disease Models, Animal
  • Erythropoietin / pharmacology*
  • Female
  • Humans
  • Hypoxia-Ischemia, Brain / genetics
  • Hypoxia-Ischemia, Brain / metabolism
  • Hypoxia-Ischemia, Brain / physiopathology
  • Hypoxia-Ischemia, Brain / prevention & control*
  • Neovascularization, Physiologic / drug effects*
  • Neuroprotective Agents / pharmacology*
  • Pregnancy
  • RNA, Messenger / metabolism
  • Rats, Sprague-Dawley
  • Recombinant Proteins / pharmacology
  • Time Factors
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism


  • Angiogenesis Inducing Agents
  • Angiopoietin-1
  • Angpt1 protein, rat
  • Antigens, CD34
  • EPO protein, human
  • Neuroprotective Agents
  • RNA, Messenger
  • Recombinant Proteins
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, rat
  • Erythropoietin