Niaspan increases angiogenesis and improves functional recovery after stroke.
OBJECTIVE
High-density lipoprotein (HDL) is implicated in the modulation of angiogenesis. In this study, we investigated whether the Niacin-mediated increase of HDL regulates angiogenesis and thereby improves functional outcome after stroke.


METHODS
Adult male rats were subjected to middle cerebral artery occlusion and were treated with or without different doses (40 and 80 mg/kg) of Niaspan, starting 24 hours after middle cerebral artery occlusion and daily for 14 days. Neurological functional tests were performed, and serum HDL level was measured. Angiogenesis and angiogenic factor expression were measured by immunohistochemistry, corneal neovascularization and capillary tube formation assay, and Western blot, respectively.


RESULTS
Niaspan significantly increased HDL level, promoted angiogenesis in the ischemic brain, and improved functional outcome after stroke. Niaspan also significantly increased corneal neovascularization compared with nontreatment control. Mechanisms underlying the Niaspan-induced vascular remodeling were investigated. Niaspan increased the expression of vascular endothelial growth factor and angiopoietin-1 (Ang1), and phosphorylation of Akt, endothelial nitric oxide synthase (NOS), and Tie2 in the ischemic brain. Niacin upregulated Ang1 expression in cultured brain endothelial cells and increased vascular endothelial growth factor, Ang1, and endothelial NOS expression in cultured astrocytes, and dose-dependently increased capillary tube formation compared with nontreatment control. Inhibition of NOS partially decreased Niacin-induced capillary tube formation. Inhibition of phosphoinositide 3-kinase or knockdown of Tie2 substantially and significantly decreased Niacin-induced capillary tube formation.


CONCLUSIONS
Niacin increases HDL and promotes angiogenesis, which may contribute to improvement of functional outcome after stroke. The Ang1/Tie2, phosphoinositide 3-kinase/Akt, and endothelial NOS pathways appear to mediate Niacin-induced angiogenesis.
Chen
Jieli
J
Department of Neurology, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, MI 48202, USA.
Cui
Xu
X
Zacharek
Alex
A
Jiang
Hao
H
Roberts
Cynthia
C
Zhang
Chunling
C
Lu
Mei
M
Kapke
Alissa
A
Feldkamp
Carolyn S
CS
Chopp
Michael
M
D042683:Angiopoietin-1 / Q000378:metabolism; D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods; D016228:Endothelial Growth Factors / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009525:Niacin / Q000627:therapeutic use*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function / Q000187:drug effects*; D020521:Stroke / Q000188:drug therapy* / Q000503:physiopathology; D014803:Vitamin B Complex / Q000627:therapeutic use*
D042683:Angiopoietin-1; D008076:Cholesterol, HDL; D016228:Endothelial Growth Factors; D014803:Vitamin B Complex; D009525:Niacin; D002784:Cholesterol; D052250:Nitric Oxide Synthase Type III; D051058:Oncogene Protein v-akt; D001973:Bromodeoxyuridine