title: Hyperlipidemia disrupts cerebrovascular reflexes and worsens ischemic perfusion defect.
abstract: Hyperlipidemia is a highly prevalent risk factor for coronary and cervical atherosclerosis and stroke. However, even in the absence of overt atherosclerosis, hyperlipidemia disrupts endothelial and smooth muscle function. We investigated the impact of hyperlipidemia on resting-brain perfusion, fundamental cerebrovascular reflexes, and dynamic perfusion defect during acute focal ischemia in hyperlipidemic apolipoprotein E knockout mice before the development of flow-limiting atherosclerotic stenoses. Despite elevated blood pressures, absolute resting cerebral blood flow was reduced by 20% in apolipoprotein E knockout compared with wild type when measured by [(14)C]-iodoamphetamine technique. Noninvasive, high spatiotemporal resolution laser speckle flow imaging revealed that the lower autoregulatory limit was elevated in apolipoprotein E knockout mice (60 vs. 40 mm Hg), and cortical hyperemic responses to hypercapnia and functional activation were attenuated by 30% and 64%, respectively. Distal middle cerebral artery occlusion caused significantly larger perfusion defects and infarct volumes in apolipoprotein E knockout compared with wild type. Cerebrovascular dysfunction showed a direct relationship to the duration of high-fat diet. These data suggest that hyperlipidemia disrupts cerebral blood flow regulation and diminishes collateral perfusion in acute stroke in the absence of hemodynamically significant atherosclerosis.
authors.affiliation: Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown 02129, Massachusetts, USA. cayata@partners.org
authors.forename: Cenk
authors.initials: C
authors.lastname: Ayata
authors.forename: Hwa Kyoung
authors.initials: HK
authors.lastname: Shin
authors.forename: Ergin
authors.initials: E
authors.lastname: Dileköz
authors.forename: Dmitriy N
authors.initials: DN
authors.lastname: Atochin
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kashiwagi
authors.forename: Katharina
authors.initials: K
authors.lastname: Eikermann-Haerter
authors.forename: Paul L
authors.initials: PL
authors.lastname: Huang
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D001921:Brain / Q000098:blood supply* / Q000378:metabolism / Q000503:physiopathology*; D002545:Brain Ischemia / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology*; D002560:Cerebrovascular Circulation; D059305:Diet, High-Fat / Q000009:adverse effects; D006949:Hyperlipidemias / Q000150:complications*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010766:Phosphorylation
chemical_list: D001057:Apolipoproteins E; D052250:Nitric Oxide Synthase Type III