Cranial burr hole with erythropoietin administration induces reverse arteriogenesis from the enriched extracranium

Neurobiol Dis. 2019 Dec:132:104538. doi: 10.1016/j.nbd.2019.104538. Epub 2019 Jul 22.

Abstract

It is challenging to revitalize ischemic penumbra after an acute stroke with intracranial perfusion insufficiency. To evaluate whether cranial burr hole and erythropoietin (EPO) generate effective revascularization, we investigated the efficacy of the augmentation method for reverse arteriogenesis from the healthy extracranial milieu. An intracranial perfusion insufficiency was created through bilateral internal carotid artery ligation (bICAL) in Sprague-Dawley rats. We administered recombinant human EPO (5000 U/kg) or saline intraperitoneally for 3 days after bICAL. Mechanical barrier disruption (MBD) was performed through a cranial burr hole with small dural cracks in the right hemisphere. The ipsilateral hemisphere with MBD grossly showed vascular networks between the extra- and intra-cranial spaces 2 weeks after the MBD procedure. It also showed significantly increased vessels in the intracranial vasculature adjacent to the MBD region (p = 0.0006). The levels of pro-angiogenic and inflammatory factors with prominent markers of vessel permeability were also significantly increased (MBD-only vs. control; Tnf-α, p = 0.0007; Vegf, p = 0.0206). In the EPO-administered group, such elevations in inflammation were significantly mitigated (combined vs. MBD-only; Tnf-α, p = 0.0008). The ipsilateral hemisphere with MBD-EPO (vs. MBD-only) showed significantly increased vessels (RECA-1, p = 0.0182) and their maturation (RECA-1/α-SMA, p = 0.0046), with upregulation of tumor growth factor-β1 (Tgf-β1, p = 0.037) and matrix metalloproteinase-2 (Mmp-2, p = 0.0488). These findings were completely blocked by minocycline (MIC) administration during in vivo (Tgf-β1, p = 0.0009; Mmp-2, p < 0.0001) and in vitro experiments (tube formation, p < 0.0001). Our data suggest that the MBD procedure (for angiogenic routes) and EPO administration (for an arteriogenic booster) are complimentary and can facilitate successfully "reverse arteriogenesis" in subjects with intracranial perfusion insufficiency.

Keywords: Angiogenesis; Arteriogenesis; Cranial burr hole; Erythropoietin; Ischemic stroke.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Cerebral Angiography / methods
  • Cerebral Arteries / diagnostic imaging*
  • Cerebral Arteries / drug effects
  • Cerebral Revascularization / methods*
  • Combined Modality Therapy / methods
  • Craniotomy / methods*
  • Erythropoietin / administration & dosage*
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Male
  • Middle Aged
  • Moyamoya Disease / diagnostic imaging*
  • Moyamoya Disease / drug therapy*
  • Prospective Studies
  • Random Allocation
  • Rats
  • Rats, Sprague-Dawley
  • Retrospective Studies
  • Skull / blood supply
  • Skull / diagnostic imaging
  • Skull / drug effects

Substances

  • EPO protein, human
  • Erythropoietin