Vascular tight junction disruption and angiogenesis in spontaneously hypertensive rat with neuroinflammatory white matter injury

Yi Yang, Shihoko Kimura-Ohba, Jeffrey F. Thompson, Victor M. Salayandia, Melissa Cossé, Limor Raz, Fakhreya Y. Jalal, Gary A. Rosenberg

Research output: Contribution to journalArticlepeer-review

37 Citations (Scopus)

Abstract

Vascular cognitive impairment is a major cause of dementia caused by chronic hypoxia, producing progressive damage to white matter (WM) secondary to blood-brain barrier (BBB) opening and vascular dysfunction. Tight junction proteins (TJPs), which maintain BBB integrity, are lost in acute ischemia. Although angiogenesis is critical for neurovascular remodeling, less is known about its role in chronic hypoxia. To study the impact of TJP degradation and angiogenesis during pathological progression of WM damage, we used the spontaneously hypertensive/stroke prone rats with unilateral carotid artery occlusion and Japanese permissive diet to model WM damage. MRI and IgG immunostaining showed regions with BBB damage, which corresponded with decreased endothelial TJPs, claudin-5, occludin, and ZO-1. Affected WM had increased expression of angiogenic factors, Ki67, NG2, VEGF-A, and MMP-3 in vascular endothelial cells and pericytes. To facilitate the study of angiogenesis, we treated rats with minocycline to block BBB disruption, reduce WM lesion size, and extend survival. Minocycline-treated rats showed increased VEGF-A protein, TJP formation, and oligodendrocyte proliferation. We propose that chronic hypoxia disrupts TJPs, increasing vascular permeability, and initiating angiogenesis in WM. Minocycline facilitated WM repair by reducing BBB damage and enhancing expression of TJPs and angiogenesis, ultimately preserving oligodendrocytes.

Original languageEnglish
Pages (from-to)95-110
Number of pages16
JournalNeurobiology of Disease
Volume114
DOIs
Publication statusPublished - Jun 2018

Keywords

  • Angiogenesis
  • BBB permeability
  • Chronic hypoxia
  • Magnetic resonance imaging
  • Spontaneously hypertensive/stroke prone rat
  • Tight junction proteins
  • Vascular cognitive impairment and dementia
  • White matter

ASJC Scopus subject areas

  • Neurology

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