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.

Decline in Sirtuin-1 expression and activity plays a critical role in blood-brain barrier permeability in aging

“…A key event for a compromised BBB is an alteration in claudin-5, a major occlusion protein for brain endothelial barrier. It has been reported that claudin-5 protein expression is changed/reduced in aging brain endothelial cells (Elahy et al, 2015;Yamazaki et al, 2016;Yang et al, 2018). In agreement, the current study showed that claudin-5 mRNA and protein slowly decline over the lifespan in mice and similarly in human brain microvessels.…”

“…claudin-5 and occludin) and uncontrolled increases in vascular permeability (BBB breakdown), to morphologically fragmented or "difficult to detect" alterations in TJ proteins that can cause small but persistent leaks with excessive perivascular build-up of fluid (BBB leakage) (Stamatovic et al, 2016). At the aging BBB, alterations in the TJ proteins claudin-5, ZO-1 and occludin have been reported with fragmented staining and various degrees of total protein loss (Elahy et al, 2015;Kaur et al, 2011;Lee et al, 2012;Yang et al, 2018). A key event for a compromised BBB is an alteration in claudin-5, a major occlusion protein for brain endothelial barrier.…”

“…Changes in the number of pericytes and morphological changes in astrocyte interactions at BBB, and ongoing inflammatory processes are considered critical for loss of BBB integrity (Bell and Zlokovic, 2009;Guerriero et al, 2017;Halliday et al, 2016;Kaur et al, 2011). Although BBB leakage might be a response to microenvironment changes in aging brain parenchyma, an important part involves "aging" processes in the brain endothelial cell and brain endothelial barrier, which could be a primary trigger of pathological cerebrovascular changes (Ueno et al, 1993;Yamazaki et al, 2016;Yang et al, 2018). How brain endothelial cells and the barrier "age" and which potential factors are involved in this process are still unclear.…”

Plasma Lipoprotein-Associated Phospholipase A2 and Superoxide Dismutase are Independent Predicators of Cognitive Impairment in Cerebral Small Vessel Disease Patients: Diagnosis and Assessment

“…Recent findings have indicated that WMHs are associated with the cognitive impairment in CSVD [4,[29][30][31], and our results (Fig. 3D, E) are consistant with these findings.…”

Neutralization of interleukin‐9 ameliorates experimental stroke by repairing the blood–brain barrierviadown‐regulation of astrocyte‐derived vascular endothelial growth factor‐A

“…Structural and functional impairment of the BBB, characterized by disruption of endothelial cell-associated connections, is one of the hallmarks of neurologic disease (36), whereas the severity of BBB disruption has been shown to correlate positively with the severity of IS (37)(38)(39). Our study also found that anti-IL-9 mAb improves the destruction of the BBB after stroke and that its mechanism is related to active repair of the damaged TJPs in brain tissue, which is different from the effects of anti-IL-9 mAb on inflammatory diseases of the CNS.…”