title: Neurovascular protection of cilostazol in stroke-prone spontaneous hypertensive rats associated with angiogenesis and pericyte proliferation.
abstract: Stroke is the major cause of death and decrease in the activities of daily living. This study sought to evaluate the effects of commonly used antiplatelet drugs on spontaneous cerebral infarction in relation to neurovascular protection associated with angiogenesis and pericyte proliferation. Stroke-prone spontaneously hypertensive rats (SHR-SP) were treated with vehicle, aspirin, clopidogrel, or cilostazol from 8 to 10 weeks of age. The interaction of neurovascular components among endothelial cells, pericytes, and astrocytic endfeet were immunohistochemically examined in brain sections. Angiogenesis associated with vascular endothelial growth factor receptor 2 (VEGFR2) and pericyte proliferation were also examined immunohistochemically. The expression and activity of matrix metalloproteinase 9 (MMP-9) were assessed immunohistochemically and by gelatin zymography. Among the antiplatelet drugs, cilostazol preserved the neurovascular unit (NVU) by preventing astrocytic endfeet or pericytes from pathological detachment found in the vehicle and aspirin treatment. Cilostazol also inhibited the expression and activity of MMP-9, which led to protection of the NVU. Furthermore, in the periinfarct area, cilostazol increased VEGFR2 expression, promoting angiogenesis through proliferation of pericytes. The present study showed a strong protection of NVU integrity by cilostazol and the promotion of angiogenesis by stimulating both endothelial VEGFR2 expression and pericyte proliferation. In addition to the antioxidative effect, these pleiotropic effects of cilostazol contribute to reduce spontaneous infarct volume and preserve motor and cognitive function in SHR-SP.
authors.affiliation: Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Omote
authors.forename: Kentaro
authors.initials: K
authors.lastname: Deguchi
authors.forename: Syoichiro
authors.initials: S
authors.lastname: Kono
authors.forename: Ning
authors.initials: N
authors.lastname: Liu
authors.forename: Wentao
authors.initials: W
authors.lastname: Liu
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kurata
authors.forename: Toru
authors.initials: T
authors.lastname: Yamashita
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Koji
authors.initials: K
authors.lastname: Abe
mesh_terms: D000818:Animals; D000941:Antigens / Q000378:metabolism; D001241:Aspirin / Q000627:therapeutic use; D002560:Cerebrovascular Circulation / Q000187:drug effects; D000077407:Cilostazol; D000077144:Clopidogrel; D004195:Disease Models, Animal; D004727:Endothelium / Q000473:pathology; D005343:Fibrinolytic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000209:etiology / Q000517:prevention & control*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D020286:Pericytes / Q000187:drug effects*; D011509:Proteoglycans / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D020521:Stroke / Q000209:etiology / Q000517:prevention & control*; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D000099216:Chondroitin Sulfate Proteoglycan 4
chemical_list: D000941:Antigens; D001241:Aspirin; D000077407:Cilostazol; D000077144:Clopidogrel; D005343:Fibrinolytic Agents; D020780:Matrix Metalloproteinase 9; D009419:Nerve Tissue Proteins; D011509:Proteoglycans; D013777:Tetrazoles; D013988:Ticlopidine; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D000099216:Chondroitin Sulfate Proteoglycan 4
keywords: SHR-SP; angiogenesis; cerebral infarction; cilostazol; neurovascular unit