The expression of matrix metalloproteinase-13 is increased in vessels with blood–brain barrier impairment in a stroke-prone hypertensive model

Abstract

We previously reported that the blood-brain barrier (BBB) function was deteriorated in vessels located in the hippocampus, but not the cerebral cortex, in 3-month-old stroke-prone spontaneously hypertensive rats (SHRSP). Recently published data suggest that matrix metalloproteinase (MMP)-2 and MMP-9 play a critical role in the BBB disruption in stroke or cerebral ischemia. In this study, we examined gene and protein expressions of MMPs in the BBB-damaged hippocampal vessels of 3-month-old SHRSP, in the cerebral cortical vessels without BBB damage of SHRSP, and in the hippocampal and cerebral cortical ones without BBB damage of 3-month-old Wistar Kyoto (WKY) rats. The expressions of MMPs were examined by real-time quantitative reverse transcriptase-PCR (RT-PCR), western blotting and immunohistochemical techniques. The gene and protein expressions of MMP-13 were significantly increased in the hippocampal samples of SHRSP compared with samples without BBB damage, such as cerebral cortical samples of SHRSP or hippocampal samples of WKY. Immunostaining of MMP-13 was seen in the cytoplasm of ED-1-positive perivascular cells in both rats and was colocalized with those of type IV collagen or osteopontin. The type IV collagen was also localized in the basement membrane. These findings indicate that the expression of MMP-13 is increased in BBB-damaged hippocampal vessels in hypertensive SHRSP compared with vessels without BBB impairment in normotensive WKY rats and may be involved in vascular remodeling. Keywords: blood-brain barrier; MMP-13; SHRSP INTRODUCTION A causative role of blood-brain barrier (BBB) impairment is suggested in the pathogenesis of vascular dementia with leakage of serum components from small vessels leading to neuronal and glial damage. 1 To clarify the roles of BBB impairment in vascular dementia, we have examined BBB function in various conditions related to vascular dementia, such as hypertension, acute ischemia with reperfusion, chronic cerebral hypoperfusion and aging with or without memory deficits. [2][3][4] Consequently, among these animal models, the most localized BBB impairment was clearly seen in the hippocampus, but not the cerebral cortex, of 3-month-old spontaneously hypertensive rats (SHR), especially of 3-month-old stroke-prone SHR (SHRSP), 4 which were established by Okamoto and Aoki 5 and are described in detail elsewhere. 6,7 It is known that the neuronal loss occurs with a reduction of gray matter volume in the CA1 subfield and dentate gyrus of the hippocampus in SHR at the age of 6 months or order, indicating that SHR can be a good animal model of vascular

Vascular dysfunction and fibrosis in stroke-prone spontaneously hypertensive rats: The aldosterone-mineralocorticoid receptor-Nox1 axis

“…Supporting this notion are our findings that vascular mRNA expression of MMP2 and MMP9 was increased in SHRSP. Similar MMP findings have been observed by others in SHRSP [30]. Although CA prevented an increase in collagen expression in SHRSP, it did not influence fibronectin expression.…”

Treatment with recombinant tissue plasminogen activator (r-TPA) induces neutrophil degranulation in vitro via defined pathways

“…The inclusion of all radiological findings (and then both symptomatic and asymptomatic lesion) certainly contributed to increase this number. Various neutrophil products have been suggested as potential mediators of reperfusion injury [48,49], but also many other risk factors were shown to be potentially associated with hemorrhagic transformation [50]. Therefore, our clinical findings remained as mainly observational and require further validation.…”

Ischemic-Reperfusion Injury Increases Matrix Metalloproteinases and Tissue Metalloproteinase Inhibitors in Fetal Sheep Brain

“…MMP-8 modulates neuroinflammation and is involved in BBB dysfunction after transient cerebral ischemia [55]. On the other hand, MMP-13 expression is increased in damaged blood vessels at the BBB and may be associated with vascular remodeling after brain ischemia [65]. Therefore, we speculate that upregulation of TIMP-1, -2, and -3 could have limited the amount of ischemia-reperfusion-related BBB disruption via MMP-8-and/or -13-dependent mechanisms in the fetal brain [4].…”