Tumor necrosis factor-α inhibition attenuates middle cerebral artery remodeling but increases cerebral ischemic damage in hypertensive rats

Abstract

Hypertension causes vascular inflammation evidenced by an increase in perivascular macrophages and proinflammatory cytokines in the arterial wall. Perivascular macrophage depletion reduced tumor necrosis factor (TNF)-α expression in cerebral arteries of hypertensive rats and attenuated inward remodeling, suggesting that TNF-α might play a role in the remodeling process. We hypothesized that TNF-α inhibition would improve middle cerebral artery (MCA) structure and reduce damage after cerebral ischemia in hypertensive rats. Six-week-old male stroke-prone spontaneously hypertensive rats (SHRSP) were treated with the TNF-α inhibitor etanercept (ETN; 1.25 mg·kg(-1)·day(-1) ip daily) or PBS (equivolume) for 6 wk. The myogenic tone generation, postischemic dilation, and passive structure of MCAs were assessed by pressure myography. Cerebral ischemia was induced by MCA occlusion (MCAO). Myogenic tone was unchanged, but MCAs from SHRSP + ETN had larger passive lumen diameter and reduced wall thickness and wall-to-lumen ratio. Cerebral infarct size was increased in SHRSP + ETN after transient MCAO, despite an improvement in dilation of nonischemic MCA. The increase in infarct size was linked to a reduction in the number of microglia in the infarct core and upregulation of markers of classical macrophage/microglia polarization. There was no difference in infarct size after permanent MCAO or when untreated SHRSP subjected to transient MCAO were given ETN at reperfusion. Our data suggests that TNF-α inhibition attenuates hypertensive MCA remodeling but exacerbates cerebral damage following ischemia/reperfusion injury likely due to inhibition of the innate immune response of the brain.

Immune responses in stroke: how the immune system contributes to damage and healing after stroke and how this knowledge could be translated to better cures?

“…These inflammatory factors are thought to contribute to post‐ischaemic neuronal damage and apoptosis, so worsening the outcome after stroke . Furthermore, genetic or pharmacological inhibition of certain microglial functions, such as proliferation and release of cytokines, may result in dampened inflammatory responses and neuronal damage after ischaemic insult . Importantly, factors such as Fas ligand released by ischaemic neurons may induce a specific pro‐inflammatory phenotype in microglia .…”

Hypertension and the Brain: A Risk Factor for More Than Heart Disease

“…Specifically, experimental studies comprising rodent models of hypertension report that targeting the ROS producing enzyme NADPH oxidase or its assembly protects from cerebrovascular oxidative stress and consequently, from alterations in endothelium-dependent relaxation and functional hyperemia [65,68,69] . To date, existing studies showing the direct effect of hypertension on cerebral artery tone [43,70] mostly describe endothelial dysfunction in isolated artery approaches; only a few studies show a direct link between endothelium-dependent vasodilation and CBF. Moreover, histological analyses of postmortem tissue from patients with severe cSVD present evidence of an intact endothelial layer in small arteries in the frontal white-matter, while showing an apparent loss of myocytes and other mural cells [71,72] .…”

Bilateral common carotid artery stenosis in normotensive rats impairs endothelium-dependent dilation of parenchymal arterioles

“…PCR was then performed using Taqman primer and probe sets in a 7,500 real time PCR system (Applied Biosystem, Foster City, CA). Fold changes in expression from Sham group were calculated using the 2 Ϫ⌬⌬CT method (30) with ␤-2-microglobulin used as endogenous control (44).…”