title: 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.
authors.affiliation: Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan pwpires@gmail.com.
authors.forename: Paulo W
authors.initials: PW
authors.lastname: Pires
authors.affiliation: Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan.
authors.forename: Saavia S
authors.initials: SS
authors.lastname: Girgla
authors.affiliation: Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Moreno
authors.affiliation: Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan.
authors.forename: Jonathon L
authors.initials: JL
authors.lastname: McClain
authors.affiliation: Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Dorrance
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D001794:Blood Pressure; D000068800:Etanercept; D006973:Hypertension / Q000188:drug therapy*; D007074:Immunoglobulin G / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology* / Q000503:physiopathology; D008264:Macrophages / Q000378:metabolism; D008297:Male; D017628:Microglia / Q000378:metabolism; D020768:Middle Cerebral Artery / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D011918:Rats, Inbred SHR; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014664:Vasodilation
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept
keywords: cerebral vascular remodeling; hypertension; ischemic stroke; macrophages/microglia; tumor necrosis factor-α