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Stroke. 2015 Jun;46(6):1657-63. doi: 10.1161/STROKEAHA.114.008062. Epub 2015 Apr 28.

Chronic Elevation of Tumor Necrosis Factor-α Mediates the Impairment of Leptomeningeal Arteriogenesis in db/db Mice.

Author information

1
From the Department of Neurology, Osaka University Graduate School of Medicine, Osaka, Japan (T.Y., Y.S., N.O., A.W., T.S., M.S., H.M.); Department of Stroke Medicine, Kawasaki Medical School, Kurashiki, Japan (Y.Y.); and Department of Neurology, Tokyo Women's Medical University, Tokyo, Japan (K.K.). yukami@neurol.med.osaka-u.ac.jp.
2
From the Department of Neurology, Osaka University Graduate School of Medicine, Osaka, Japan (T.Y., Y.S., N.O., A.W., T.S., M.S., H.M.); Department of Stroke Medicine, Kawasaki Medical School, Kurashiki, Japan (Y.Y.); and Department of Neurology, Tokyo Women's Medical University, Tokyo, Japan (K.K.).

Abstract

BACKGROUND AND PURPOSE:

Leptomeningeal collateral growth is a key factor that defines the severity of ischemic stroke. Patients with stroke generally have vascular risk factors, such as diabetes mellitus; however, consensus is lacking on how diabetes mellitus affects leptomeningeal arteriogenesis. We investigate the influence of diabetes mellitus on the leptomeningeal arteriogenesis.

METHODS:

We measured the vessel diameter of the leptomeningeal anastomoses 14 days after the common carotid artery occlusion in db/db, db/+, and streptozotocin-induced hyperglycemic mice. In another set of these mice, we measured the infarct volume attributed to subsequent middle cerebral artery occlusion 14 days after the common carotid artery occlusion. Mac-2-positive cells on the dorsal brain surface and the mRNA expression of several macrophage-related factors in the cerebral cortex were examined. Finally, we tested whether the leptomeningeal arteriogenesis could be restored by pharmaceutical intervention in the db/db mice.

RESULTS:

Cerebral hypoperfusion led to significant ipsilateral leptomeningeal collateral growth in db/+ mice and streptozotocin-induced hyperglycemic mice. The collateral growth contributed to reduced infarct volume. In contrast, leptomeningeal arteriogenesis was impaired in the db/db mice. The number of Mac-2-positive cells was increased and tumor necrosis factor-α mRNA expression was induced after common carotid artery occlusion in the db/+ mice. However, these responses were not observed in the db/db mice. Administration of the tumor necrosis factor-α inhibitor etanercept before common carotid artery occlusion restored the hypoperfusion-induced leptomeningeal collateral growth in db/db mice.

CONCLUSIONS:

These results indicate that leptomeningeal arteriogenesis is impaired in db/db mice and that suppression of the tumor necrosis factor-α response to hypoperfusion is the major contributing factor.

KEYWORDS:

animal models; collateral circulation; diabetes mellitus; tumor necrosis factor-α

PMID:
25922509
DOI:
10.1161/STROKEAHA.114.008062
[Indexed for MEDLINE]

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