Endogenous endothelial progenitor cells participate in neovascularization via CXCR4/SDF-1 axis and improve outcome after stroke

CNS Neurosci Ther. 2014 May;20(5):460-8. doi: 10.1111/cns.12238. Epub 2014 Mar 2.

Abstract

Aim: To study whether endogenous endothelial progenitor cells (EPCs) are involved in neovascularization after stroke.

Materials and methods: Animal stroke models were established by subjecting male SD rats to permanent middle cerebral artery occlusion (pMCAO). Vessels in ischemic boundary zone (IBZ) were stained with antibody against laminin at 1 to 21 days after pMCAO. EPCs and newly formed vessels were identified by staining with special markers. After inhibiting recruitment of EPCs with AMD3100, a CXCR4 antagonist, endogenous EPCs, capillary density, cerebral blood flow (CBF) in IBZ, and neurobehavioral functions were assessed by staining, FITC-dextran, laser-Doppler perfusion monitor, and neurologic severity score.

Results: After pMCAO, vessels were found in IBZ at day 3, reaching a peak at day 14. The change in number of laminin-positive cells showed a similar pattern with that of vessels. Apart from few endothelial cells, most of laminin-positive cells were endogenous EPCs. After treatment with AMD3100, the number of endogenous EPCs, capillary density, and CBF in IBZ were significantly reduced, and neurobehavioral functions were worse as compared with the normal saline group.

Conclusions: Our findings suggested that endogenous EPCs participated in the neovascularization via CXCR4/SDF-1 axis after pMCAO and mobilizing endogenous EPCs could be a treatment alternative for stroke.

Keywords: CXCR4; EPCs; Neovascularization; Stroke.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / pharmacology
  • Animals
  • Brain / blood supply
  • Brain / drug effects
  • Brain / pathology
  • Brain / physiopathology*
  • Brain Ischemia / etiology
  • Brain Ischemia / pathology
  • Brain Ischemia / physiopathology
  • Capillaries / drug effects
  • Capillaries / pathology
  • Capillaries / physiopathology
  • Cerebrovascular Circulation
  • Chemokine CXCL12 / metabolism*
  • Disease Models, Animal
  • Endothelial Progenitor Cells / drug effects
  • Endothelial Progenitor Cells / pathology
  • Endothelial Progenitor Cells / physiology*
  • Heterocyclic Compounds / pharmacology
  • Infarction, Middle Cerebral Artery / complications
  • Infarction, Middle Cerebral Artery / pathology
  • Infarction, Middle Cerebral Artery / physiopathology
  • Male
  • Neovascularization, Physiologic / drug effects
  • Neovascularization, Physiologic / physiology*
  • Rats, Sprague-Dawley
  • Receptors, CXCR4 / antagonists & inhibitors
  • Receptors, CXCR4 / metabolism*
  • Severity of Illness Index
  • Stroke / etiology
  • Stroke / pathology
  • Stroke / physiopathology*

Substances

  • Angiogenesis Inhibitors
  • CXCL12 protein, rat
  • Chemokine CXCL12
  • Cxcr4 protein, rat
  • Heterocyclic Compounds
  • Receptors, CXCR4
  • plerixafor