Chronic Elevation of Tumor Necrosis Factor-α Mediates the Impairment of Leptomeningeal Arteriogenesis in db/db Mice.
OBJECTIVE
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.
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.
Toshiro
T
Yukami
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.).
Yoshiki
Y
Yagita
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.).
Yukio
Y
Sugiyama
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.).
Naoki
N
Oyama
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.).
Akihiro
A
Watanabe
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.).
Tsutomu
T
Sasaki
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.).
Manabu
M
Sakaguchi
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.).
Hideki
H
Mochizuki
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.).
Kazuo
K
Kitagawa
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002340:Carotid Artery Diseases / Q000097:blood* / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D000068800:Etanercept; D006943:Hyperglycemia / Q000097:blood / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D007074:Immunoglobulin G / Q000494:pharmacology; D020244:Infarction, Middle Cerebral Artery / Q000097:blood* / Q000188:drug therapy / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D018919:Neovascularization, Physiologic; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000097:blood* / Q000235:genetics
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept
animal models; collateral circulation; diabetes mellitus; tumor necrosis factor-α