title: Diabetic microangiopathy: impact of impaired cerebral vasoreactivity and delayed angiogenesis after permanent middle cerebral artery occlusion on stroke damage and cerebral repair in mice.
abstract: Diabetes increases the risk of stroke by three, increases related mortality, and delays recovery. We aimed to characterize functional and structural alterations in cerebral microvasculature before and after experimental cerebral ischemia in a mouse model of type 1 diabetes. We hypothesized that preexisting brain microvascular disease in patients with diabetes might partly explain increased stroke severity and impact on outcome. Diabetes was induced in 4-week-old C57Bl/6J mice by intraperitoneal injections of streptozotocin (60 mg/kg). After 8 weeks of diabetes, the vasoreactivity of the neurovascular network to CO2 was abolished and was not reversed by nitric oxide (NO) donor administration; endothelial NO synthase (eNOS) and neuronal NO synthase (nNOS) mRNA, phospho-eNOS protein, nNOS, and phospho-nNOS protein were significantly decreased; angiogenic and vessel maturation factors (vascular endothelial growth factor a [VEGFa], angiopoietin 1 (Ang1), Ang2, transforming growth factor-β [TGF-β], and platelet-derived growth factor-β [PDGF-β]) and blood-brain barrier (BBB) occludin and zona occludens 1 (ZO-1) expression were significantly decreased; and microvessel density was increased without changes in ultrastructural imaging. After permanent focal cerebral ischemia induction, infarct volume and neurological deficit were significantly increased at D1 and D7, and neuronal death (TUNEL+ / NeuN+ cells) and BBB permeability (extravasation of Evans blue) at D1. At D7, CD31+ / Ki67+ double-immunolabeled cells and VEGFa and Ang2 expression were significantly increased, indicating delayed angiogenesis. We show that cerebral microangiopathy thus partly explains stroke severity in diabetes.
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Angiogenesis and Translational Research Center, INSERM U965, Paris, France.
authors.forename: Marine
authors.initials: M
authors.lastname: Poittevin
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Angiogenesis and Translational Research Center, INSERM U965, Paris, France Service de Physiologie Clinique, AP-HP, Hôpital Lariboisière, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Bonnin
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Angiogenesis and Translational Research Center, INSERM U965, Paris, France.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Pimpie
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Angiogenesis and Translational Research Center, INSERM U965, Paris, France.
authors.forename: Léa
authors.initials: L
authors.lastname: Rivière
authors.affiliation: Université Paris Sud, UMR 8081 CNRS, Orsay, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Sebrié
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Angiogenesis and Translational Research Center, INSERM U965, Paris, France.
authors.forename: Anthony
authors.initials: A
authors.lastname: Dohan
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Angiogenesis and Translational Research Center, INSERM U965, Paris, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Pocard
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, INSERM U1141 and DHU Protect, Paris, France.
authors.forename: Christiane
authors.initials: C
authors.lastname: Charriaut-Marlangue
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Angiogenesis and Translational Research Center, INSERM U965, Paris, France Service de Physiologie Clinique, AP-HP, Hôpital Lariboisière, Paris, France nathalie.kubis@lrb.aphp.fr.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Kubis
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology*; D003925:Diabetic Angiopathies / Q000378:metabolism* / Q000473:pathology*; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism* / Q000473:pathology*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D052248:Nitric Oxide Synthase Type I / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D012259:Ribonuclease, Pancreatic / Q000235:genetics / Q000378:metabolism; D020521:Stroke / Q000378:metabolism* / Q000473:pathology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D062826:Zonula Occludens-1 Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C569043:Tjp1 protein, mouse; D042461:Vascular Endothelial Growth Factor A; D062826:Zonula Occludens-1 Protein; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; C099439:Ang2 protein, mouse; D012259:Ribonuclease, Pancreatic