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. 2014 Jan;122(1):79-86.
doi: 10.1289/ehp.1307151. Epub 2013 Nov 15.

Long-term exposure to concentrated ambient PM2.5 increases mouse blood pressure through abnormal activation of the sympathetic nervous system: a role for hypothalamic inflammation

Zhekang Ying  1 , Xiaohua Xu, Yuntao Bai, Jixin Zhong, Minjie Chen, Yijia Liang, Jinzhuo Zhao, Dongyao Liu, Masako Morishita, Qinghua Sun, Catherine Spino, Robert D Brook, Jack R Harkema, Sanjay Rajagopalan
Affiliations

Long-term exposure to concentrated ambient PM2.5 increases mouse blood pressure through abnormal activation of the sympathetic nervous system: a role for hypothalamic inflammation

Zhekang Ying et al. Environ Health Perspect. 2014 Jan.

Abstract

Background: Exposure to particulate matter≤2.5 μm in diameter (PM2.5) increases blood pressure (BP) in humans and animal models. Abnormal activation of the sympathetic nervous system may have a role in the acute BP response to PM2.5 exposure. The mechanisms responsible for sympathetic nervous system activation and its role in chronic sustenance of hypertension in response to PM2.5 exposure are currently unknown.

Objectives: We investigated whether central nervous system inflammation may be implicated in chronic PM2.5 exposure-induced increases in BP and sympathetic nervous system activation.

Methods: C57BL/6J mice were exposed to concentrated ambient PM2.5 (CAPs) for 6 months, and we analyzed BP using radioactive telemetric transmitters. We assessed sympathetic tone by measuring low-frequency BP variability (LF-BPV) and urinary norepinephrine excretion. We also tested the effects of acute pharmacologic inhibitors of the sympathetic nervous system and parasympathetic nervous system.

Results: Long-term CAPs exposure significantly increased basal BP, paralleled by increases in LF-BPV and urinary norepinephrine excretion. The increased basal BP was attenuated by the centrally acting α2a agonist guanfacine, suggesting a role of increased sympathetic tone in CAPs exposure-induced hypertension. The increase in sympathetic tone was accompanied by an inflammatory response in the arcuate nucleus of the hypothalamus, evidenced by increased expression of pro-inflammatory genes and inhibitor kappaB kinase (IKK)/nuclear factor-kappaB (NF-κB) pathway activation.

Conclusion: Long-term CAPs exposure increases BP through sympathetic nervous system activation, which may involve hypothalamic inflammation.

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Conflict of interest statement

This publication’s contents are solely the responsibility of the grantee and do not necessarily represent the official views of the U.S. EPA. The U.S. EPA does not endorse the purchase of any commercial products or services mentioned in the publication.

The authors declare they have no actual or potential competing financial interests.

Figures

Figure 1
Figure 1
CAPs exposure increases basal BP in C57BL/6J mice. (A) Diagram of the experimental time scheme. Abbreviations: A, atropine; G, guanfacine; P, propranolol; S, air-jet stress. After exposure to FA or CAPs for 6 months, mice (n = 6/group) were implanted with DSI radiotelemetry transmitters, and the basal BP was analyzed after recovery from surgery. (B) Representative recordings: the basal BP was recorded after daily FA or CAPs exposure for approximately 18 hr/day for 3 continuous days. Quantization of 16-hr MAP (1700–0900 hours) (C), HR (D), and mouse activity (E). *p < 0.05, compared with FA using two-way ANOVA.
Figure 2
Figure 2
CAPs exposure induces resistance arterial dysfunction. After sacrifice, mouse mesenteric arteries were isolated and mounted onto a wire myograph, and responses to phenylephrine (A), acetylcholine (B), and U-46619 (C) were analyzed. *p < 0.05, compared with FA using two-way ANOVA.
Figure 3
Figure 3
CAPs exposure increases sympathetic tone. (A) The LF-BPV was calculated from the 3 days of basal BP recording. (B) Urine of FA- and CAPs-exposed mice was collected and norepinephrine excretion was assessed. After analysis of the basal BP in FA- and CAPs-exposed mice with radiotelemetry transmitter, mice were treated with propranolol (C), atropine (D), and guanfacine (E), and changes in either HR (propranolol and atropine) or BP (guanfacine) is presented. NE, norepinephrine. *p < 0.05, compared with FA using Student’s t-test.
Figure 4
Figure 4
CAPs exposure increases stress-induced hypertension. FA- and CAPs-exposed mice were stimulated with air jet, and BP response was analyzed with radiotelemetry transmitter. (A) The BP response curve. (B) The peak increase in BP. (C) The area under the BP response curve (AUC). AU, arbitrary units. *p < 0.05, compared with FA using Student’s t-test.
Figure 5
Figure 5
CAPs exposure induces hypothalamic inflammation. (A) FA- and CAPs-exposed mice were sacrificed, and hypothalamic expression of pro-inflammatory genes was analyzed by RT-PCR. Immunostaining of mouse hypothalamus with anti-phospho-IKK2 (B) and anti-c-fos (C). Abbreviations: ARC, arcuate nucleus; AU, arbitrary units; PVN, paraventricular nucleus. In B and C, bar = 25 μm. *p < 0.05, compared with FA using Student’s t-test.
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