Microglia Participate in Neurogenic Regulation of Hypertension

Shen, Xiao Z.; Li, You; Li, Liang; Shah, Kandarp H.; Bernstein, Kenneth E.; Lyden, Patrick D.; Shi, Peng

doi:10.1161/hypertensionaha.115.05333

Cited by 121 publications

(115 citation statements)

References 28 publications

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“…These studies showed changes in microglial morphology (enlarged soma, process retraction) and increased production of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) [16][17][18]. Our results confirm that pressive Ang II leads to cerebral gliosis and extends this finding to another brain region, namely the hippocampus.…”

Section: Discussionsupporting

confidence: 85%

“…We decided to examine TNF-α in more detail rather than IL-6, based on previous evidence that hypothalamic microglia isolated from Ang II-treated mice exhibit a significant increase in TNF-α expression and a milder increase in IL-6 [17,18]. In line with the proposed hypothesis, ELISA analysis of hippocampal homogenates revealed a significant increase in TNF-α levels in mice infused with Ang II 1000 ng/kg/min compared to controls (p = 0.040, Fig.…”

Section: Effect Of Ang II On Tnf-α Production In the Hippocampusmentioning

confidence: 99%

“…Using anti-inflammatory approaches (with minocycline or IL-10 administered directly to the brain) or depleting microglia by intra-cerebro-ventricular administration of diphtheria toxin (DT) to transgenic CD11b-DT receptor mice, these studies have shown that inflammation and microglia play a central role in the development of high blood pressure in mice and rats [16,17]. While finding that inflammation influenced blood pressure, they also showed that hypertension, which was achieved via systemic infusion of angiotensin II (Ang II), was capable of producing increases in microglial density, soma enlargement, and reductions in microglial process length, as well as greater production of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) in this brain region [16][17][18].…”

Section: Introductionmentioning

confidence: 99%

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Differential effect of angiotensin II and blood pressure on hippocampal inflammation in mice

Iulita

Vallerand

Beauvillier

et al. 2018

J Neuroinflammation

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Background: Angiotensin II (Ang II), a peptide hormone involved in the development of hypertension, causes systemic and cerebral inflammation, affecting brain regions important for blood pressure control. The cause-andeffect relationship between hypertension and inflammation is two-way, but the role of blood pressure in the induction of cerebral inflammation is less clear. The vulnerability of specific brain regions, particularly those important for memory, is also of interest. Methods: We used molecular biology approaches, immunohistochemistry, and electron microscopy to examine the interdependence between the hypertensive and pro-inflammatory effects of Ang II. We examined the effect of blood pressure by administering a subpressive (200 ng/kg/min) or a pressive Ang II dose (1000 or 1900 ng/kg/min) with and without hydralazine (150 mg/L) for 1 week and used phenylephrine to increase blood pressure independently of the renin-angiotensin system.

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Section: Discussionsupporting

confidence: 85%

Section: Effect Of Ang II On Tnf-α Production In the Hippocampusmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Differential effect of angiotensin II and blood pressure on hippocampal inflammation in mice

Iulita

Vallerand

Beauvillier

et al. 2018

J Neuroinflammation

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“…Our results provide further evidence that they do not. Because it has recently been discovered that microglia mediate neurogenic hypertension and that their depletion leads to significantly attenuated blood pressure (36), the triggering of microglia apoptosis could be an unidentified reason why nimodipine treatment is highly effective in hypertension. In addition to the apoptosis-inducing effect, we obtained evidence that nimodipine modulates the proinflammatory activity of surviving microglial cells.…”

Section: Discussionmentioning

confidence: 99%

Nimodipine fosters remyelination in a mouse model of multiple sclerosis and induces microglia-specific apoptosis

Schampel

Volovitch

Koeniger

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Despite continuous interest in multiple sclerosis (MS) research, there is still a lack of neuroprotective strategies, because the main focus has remained on modulating the immune response. Here we performed in-depth analysis of neurodegeneration in experimental autoimmune encephalomyelitis (EAE) and in in vitro studies regarding the effect of the well-established L-type calcium channel antagonist nimodipine. Nimodipine treatment attenuated clinical EAE and spinal cord degeneration and promoted remyelination. Surprisingly, we observed calcium channel-independent effects on microglia, resulting in apoptosis. These effects were cell-type specific and irrespective of microglia polarization. Apoptosis was accompanied by decreased levels of nitric oxide (NO) and inducible NO synthase (iNOS) in cell culture as well as decreased iNOS and reactive oxygen species levels in EAE. In addition, increased numbers of Olig2 + APC + oligodendrocytes were detected. Overall, nimodipine application seems to generate a favorable environment for regenerative processes and therefore could be a treatment option for MS, because it combines features of immunomodulation with beneficial effects on neuroregeneration.M ultiple sclerosis (MS) is the most prevalent neurological disease of the CNS in young adults and is characterized by inflammation, demyelination, and axonal pathology (1) that result in multiple neurological and cognitive deficits (1-3). Intensive MS research studies have investigated modulating the immune system (4). Common therapeutic strategies are effective in slowing disease progression and attenuating the symptoms, but they cannot cure the disease. The option of preventing neurodegeneration early on would be a valuable addendum to customary treatment (4). Here we suggest that application of nimodipine could be an elegant way to target both neuroinflammation and neurodegeneration. The dihydropyridine nimodipine is commonly known as a 1.2 voltagegated L-type calcium channel antagonist and is used to treat hypertension and other cardiovascular diseases (5, 6). It also is used to prevent vasospasms after subarachnoidal hemorrhage (5) because of its high affinity for the CNS (7-9). Current research trials are examining its effects on brain injury, epilepsy, cognitive performance, and behavioral effects (6,7,10,11). Its influence on oxidative stress, neuronal survival, synaptic plasticity, and aging also are being investigated, especially within the hippocampus (10, 12). In addition, it was recently shown that the risk of suffering from Parkinson's disease was decreased under treatment with dihydropyridines (13). These studies suggest that nimodipine might have beneficial effects in MS as well, although its role in neurodegenerative diseases that are mediated by inflammatory events has not been well established (6). So far, nimodipine-mediated effects in the CNS have been claimed to result mainly from the modulation of neuronal activity, and studies on the potential effects of nimodipine on (micro)glia have not yet been conduct...

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“…Both M1 (MHC II, CCR7, interferon-γ receptor, and iNOS) and M2 markers (CD36, mannose receptor, Tie2, and IL-4 receptor α) were upregulated in microglia from hypertensive mice, but not in monocytes, which may be explained by the neurogenic regulation of hypertension [232]. Other studies demonstrated that proinflammatory M1 macrophages are predominant in the aortas stimulated by angiotensin-II for 7 days [233,234]; however, prolonged infusion of angiotensin-II for 14 to 28 days recruited Ly-6C hi monocytes that differentiated into M2 macrophages [235].…”

Section: Hypertensionmentioning

confidence: 92%

Microglia and Monocyte-Derived Macrophages in Stroke

2016

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Historically, the brain has been considered an immune-privileged organ separated from the peripheral immune system by the blood-brain barrier. However, immune responses do occur in the brain in neurological conditions in which the integrity of the blood-brain barrier is compromised, exposing the brain to peripheral antigens and endogenous danger signals. While most of the associated pathological processes occur in the central nervous system, it is now clear that peripheral immune cells, especially mononuclear phagocytes, that infiltrate into the injury site play a key role in modulating the progression of primary brain injury development. As inflammation is a necessary and critical component for the subsequent injury resolution process, understanding the contribution of mononuclear phagocytes on the regulation of inflammatory responses may provide novel approaches for potential therapies. Furthermore, predisposed comorbid conditions at the time of stroke cause the alteration of stroke-induced immune and inflammatory responses and subsequently influence stroke outcome. In this review, we summarize a role for microglia and monocytes/macrophages in acute ischemic stroke in the context of normal and metabolically compromised conditions.

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Microglia Participate in Neurogenic Regulation of Hypertension

Cited by 121 publications

References 28 publications

Differential effect of angiotensin II and blood pressure on hippocampal inflammation in mice

Differential effect of angiotensin II and blood pressure on hippocampal inflammation in mice

Nimodipine fosters remyelination in a mouse model of multiple sclerosis and induces microglia-specific apoptosis

Microglia and Monocyte-Derived Macrophages in Stroke

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