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J Neuroinflammation. 2019 Apr 10;16(1):79. doi: 10.1186/s12974-019-1467-7.

Transiently proliferating perivascular microglia harbor M1 type and precede cerebrovascular changes in a chronic hypertension model.

Author information

1
Department of Neurology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho Kamigyo-ku, Kyoto, 602-8566, Japan.
2
Department of Anatomy and Neurobiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
3
Department of Clinical Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University, Kyoto, Japan.
4
Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
5
Department of Applied Biology, Kyoto Institute of Technology, Kyoto, Japan.
6
Department of Pharmacology and Toxicology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands.
7
Department of Neuroscience, School for Mental Health and Neuroscience, Maastricht University Medical Center +, Maastricht, The Netherlands.
8
Department of Neurology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho Kamigyo-ku, Kyoto, 602-8566, Japan. mizuno@koto.kpu-m.ac.jp.

Abstract

BACKGROUND:

Microglia play crucial roles in the maintenance of brain homeostasis. Activated microglia show a biphasic influence, promoting beneficial repair and causing harmful damage via M2 and M1 microglia, respectively. It is well-known that microglia are initially activated to the M2 state and subsequently switch to the M1 state, called M2-to-M1 class switching in acute ischemic models. However, the activation process of microglia in chronic and sporadic hypertension remains poorly understood. We aimed to clarify the process using a chronic hypertension model, the deoxycorticosterone acetate (DOCA)-salt-treated Wistar rats.

METHODS:

After unilateral nephrectomy, the rats were randomly divided into DOCA-salt, placebo, and control groups. DOCA-salt rats received a weekly subcutaneous injection of DOCA (40 mg/kg) and were continuously provided with 1% NaCl in drinking water. Placebo rats received a weekly subcutaneous injection of vehicle and were provided with tap water. Control rats received no administration of DOCA or NaCl. To investigate the temporal expression profiles of M1- and M2-specific markers for microglia, the animals were subjected to the immunohistochemical and biochemical studies after 2, 3, or 4 weeks DOCA-salt treatment.

RESULTS:

Hypertension occurred after 2 weeks of DOCA and salt administration, when round-shaped microglia with slightly shortened processes were observed juxtaposed to the vessels, although the histopathological findings were normal. After 3 weeks of DOCA and salt administration, M1-state perivascular and parenchyma microglia significantly increased, when local histopathological findings began to be observed but cerebrovascular destruction did not occur. On the other hand, M2-state microglia were never observed around the vessels at this period. Interestingly, prior to M1 activation, about 55% of perivascular microglia transiently expressed Ki-67, one of the cell proliferation markers.

CONCLUSIONS:

We concluded that the resting perivascular microglia directly switched to the pro-inflammatory M1 state via a transient proliferative state in DOCA-salt rats. Our results suggest that the activation machinery of microglia in chronic hypertension differs from acute ischemic models. Proliferative microglia are possible initial key players in the development of hypertension-induced cerebral vessel damage. Fine-tuning of microglia proliferation and activation could constitute an innovative therapeutic strategy to prevent its development.

KEYWORDS:

Cerebral small vessel disease; Chronic hypertension; Neuroinflammation; Perivascular microglia; Proliferation

PMID:
30971251
DOI:
10.1186/s12974-019-1467-7
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