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

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.

• Authors: Yi Yang, Shihoko Kimura-Ohba, Jeffrey F Thompson, Victor M Salayandia, Melissa Cossé, Limor Raz, Fakhreya Y Jalal, Gary A Rosenberg
• Journal: Neurobiology of disease (Neurobiol Dis) Vol. 114 Pg. 95-110 (06 2018) ISSN: 1095-953X [Electronic] United States
• PMID: 29486300 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Topics

• Animals
• Blood-Brain Barrier (diagnostic imaging, metabolism)
• Capillary Permeability (physiology)
• Endothelium, Vascular (diagnostic imaging, metabolism)
• Hypertension (diagnostic imaging, metabolism)
• Inflammation (diagnostic imaging, metabolism)
• Male
• Neovascularization, Pathologic (diagnostic imaging, metabolism)
• Rats
• Rats, Inbred SHR
• Rats, Inbred WKY
• Tight Junctions (metabolism)
• White Matter (diagnostic imaging, injuries, metabolism)