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Endothelial cell Pannexin1 modulates severity of ischemic stroke by regulating cerebral inflammation and myogenic tone
Miranda E Good, … , Zhiyi Zuo, Brant E. Isakson
Miranda E Good, … , Zhiyi Zuo, Brant E. Isakson
Published March 22, 2018
Citation Information: JCI Insight. 2018;3(6):e96272. https://doi.org/10.1172/jci.insight.96272.
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Research Article Neuroscience

Endothelial cell Pannexin1 modulates severity of ischemic stroke by regulating cerebral inflammation and myogenic tone

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Abstract

Ischemic stroke is a leading cause of morbidity and mortality in the US; however, there currently exists only one effective acute pharmacological therapeutic intervention. Purinergic signaling has been shown to regulate vascular function and pathological processes, including inflammation and arterial myogenic reactivity, and plays a role in ischemic stroke outcome. Purinergic signaling requires extracellular purines; however, the mechanism of purine release from cells is unclear. Pannexin1 (Panx1) channels are potentially novel purine release channels expressed throughout the vascular tree that couples regulated purine release with purinergic signaling. Therefore, we examined the role of smooth muscle and endothelial cell Panx1, using conditional cell type–specific transgenic mice, in cerebral ischemia/reperfusion injury outcomes. Deletion of endothelial cell Panx1, but not smooth muscle cell Panx1, significantly reduced cerebral infarct volume after ischemia/reperfusion. Infiltration of leukocytes into brain tissue and development of cerebral myogenic tone were both significantly reduced when mice lacked endothelial Panx1. Panx1 regulation of myogenic tone was unique to the cerebral circulation, as mesenteric myogenic reactivity and blood pressure were independent of endothelial Panx1. Overall, deletion of endothelial Panx1 mitigated cerebral ischemic injury by reducing inflammation and myogenic tone development, indicating that endothelial Panx1 is a possible novel target for therapeutic intervention of ischemic stroke.

Authors

Miranda E Good, Stephanie A. Eucker, Jun Li, Hannah M. Bacon, Susan M. Lang, Joshua T. Butcher, Tyler J. Johnson, Ronald P. Gaykema, Manoj K. Patel, Zhiyi Zuo, Brant E. Isakson

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Figure 1

Panx1 is expressed in EC and SMC of cerebral arteries with successful knockdown in EC and SMC transgenic mice.

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Panx1 is expressed in EC and SMC of cerebral arteries with successful kn...
In all sections, Panx1 (Panx1-CT antibody) was stained in red and nuclei (DAPI) in blue. (A) Low-magnification view of brain section. Arrow indicates cerebral artery in field of view. (B) Zoomed-in cross section of the somatosensory cortex neurons sections were stained for Panx1 and neurons using NeuN antibody (green). (C) Isolated control PCA sections were collected from Panx1 fl/fl (control) at low magnification, as well as (D) secondary antibody only and (E) rabbit IgG. (F) High magnification of control PCA and PCA from mice that had genotypes of SMC Panx1 Δ/Δ (G), and EC Panx1 Δ/Δ (H). In D and E, the autofluorescence of the internal elastic lamina is in green and separates the EC (E) and SMC (S) layers. In F–H the separation between EC and SMC, the IEL, is indicated by a dotted line. Asterisks indicate lumen of artery in each image. (A and B) Scale bars: 100 μm. (C–E) Scale bar: 20 μm. (F–H) Scale bar: 10 μm.

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