title: Bilateral common carotid artery stenosis in normotensive rats impairs endothelium-dependent dilation of parenchymal arterioles.
abstract: Chronic cerebral hypoperfusion is a risk factor for cognitive impairment. Reduced blood flow through the common carotid arteries induced by bilateral carotid artery stenosis (BCAS) is a physiologically relevant model of chronic cerebral hypoperfusion. We hypothesized that BCAS in 20-wk-old Wistar-Kyoto (WKY) rats would impair cognitive function and lead to reduced endothelium-dependent dilation and outward remodeling in the parenchymal arterioles (PAs). After 8 wk of BCAS, both short-term memory and spatial discrimination abilities were impaired. In vivo assessment of cerebrovascular reserve capacity showed a severe impairment after BCAS. PA endothelial function and structure were assessed by pressure myography. BCAS impaired endothelial function in PAs, as evidenced by reduced dilation to carbachol. Addition of nitric oxide synthase and cyclooxygenase inhibitors did not change carbachol-mediated dilation in either group. Inhibiting CYP epoxygenase, the enzyme that produces epoxyeicosatrienoic acid (EETs), a key determinant of endothelium-derived hyperpolarizing factor (EDHF)-mediated dilation, abolished dilation in PAs from Sham rats, but had no effect in PAs from BCAS rats. Expression of TRPV4 channels, a target for EETs, was decreased and maximal dilation to a TRPV4 agonist was attenuated after BCAS. Together these data suggest that EET-mediated dilation is impaired in PAs after BCAS. Thus impaired endothelium-dependent dilation in the PAs may be one of the contributing factors to the cognitive impairment observed after BCAS.
authors.affiliation: Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan matinnus@msu.edu.
authors.forename: Nusrat
authors.initials: N
authors.lastname: Matin
authors.affiliation: Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan.
authors.forename: Courtney
authors.initials: C
authors.lastname: Fisher
authors.affiliation: Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan.
authors.forename: William F
authors.initials: WF
authors.lastname: Jackson
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; D001160:Arterioles / Q000378:metabolism / Q000503:physiopathology*; D001522:Behavior, Animal; D001921:Brain / Q000098:blood supply*; D017536:Carotid Artery, Common / Q000503:physiopathology* / Q000601:surgery; D016893:Carotid Stenosis / Q000150:complications / Q000503:physiopathology*; D002560:Cerebrovascular Circulation; D002561:Cerebrovascular Disorders / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology* / Q000523:psychology; D003071:Cognition; D003072:Cognition Disorders / Q000209:etiology / Q000503:physiopathology / Q000523:psychology; D004195:Disease Models, Animal; D015777:Eicosanoids / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism / Q000503:physiopathology*; D008026:Ligation; D008570:Memory, Short-Term; D011921:Rats, Inbred WKY; D012039:Regional Blood Flow; D013037:Spatial Behavior; D050916:TRPV Cation Channels / Q000378:metabolism; D013997:Time Factors; D014664:Vasodilation
chemical_list: D015777:Eicosanoids; D050916:TRPV Cation Channels; C486577:Trpv4 protein, rat
keywords: cerebral microcirculation; endothelium-dependent dilation; epoxyeicosatrienoic acid; parenchymal arterioles; posterior communicating artery; vascular remodeling