Partial loss of VE-cadherin improves long-term outcome and cerebral blood flow after transient brain ischemia in mice

BMC Neurol. 2016 Aug 18;16(1):144. doi: 10.1186/s12883-016-0670-8.

Abstract

Background: VE-cadherin is the chief constituent of endothelial adherens junctions. However, the role of VE-cadherin in the pathogenesis of cerebrovascular diseases including brain ischemia has not yet been investigated.

Methods: VE-cadherin heterozygous (VEC(+/-)) mice and wildtype controls were subjected to transient brain ischemia by 30 min filamentous middle cerebral artery occlusion (MCAo)/reperfusion.

Results: Acute lesion sizes as assessed by MR-imaging on day 3 did not differ between genotypes. Unexpectedly, however, partial loss of VE-cadherin resulted in long-term stroke protection measured histologically on day 28. Equally surprisingly, VEC(+/-) mice displayed no differences in post-stroke angiogenesis compared to littermate controls, but showed increased absolute regional cerebral blood flow in ischemic striatum at four weeks. The early induction of VE-cadherin mRNA transcription after stroke was reduced in VEC(+/-) mice. By contrast, N-cadherin and β-catenin mRNA expression showed a delayed, but sustained, upregulation up to 28 days after MCAo, which was increased in VEC(+/-) mice. Furthermore, partial loss of VE-cadherin resulted in a pattern of elevated ischemia-triggered mRNA transcription of pericyte-related molecules α-smooth muscle actin (α-SMA), aminopeptidase N (CD13), and platelet-derived growth factor receptor β (PDGFR-β).

Conclusions: Partial loss of VE-cadherin results in long term stroke protection. On the cellular and molecular level, this effect appears to be mediated by improved endothelial/pericyte interactions and the resultant increase in cerebral blood flow. Our study reinforces accumulating evidence that long-term stroke outcome depends critically on vascular mechanisms.

Keywords: Adhesion molecule; Angiogenesis; Cerebral ischemia; Endothelium; Pericyte; Stroke.

MeSH terms

  • Animals
  • Antigens, CD / metabolism*
  • Cadherins / metabolism*
  • Cerebrovascular Circulation / physiology*
  • Disease Models, Animal
  • Endothelium, Vascular / metabolism*
  • Infarction, Middle Cerebral Artery / complications
  • Infarction, Middle Cerebral Artery / metabolism*
  • Infarction, Middle Cerebral Artery / physiopathology
  • Ischemic Attack, Transient / etiology
  • Ischemic Attack, Transient / metabolism*
  • Ischemic Attack, Transient / physiopathology
  • Male
  • Mice
  • Mice, Transgenic
  • Pericytes / metabolism*

Substances

  • Antigens, CD
  • Cadherins
  • cadherin 5