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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:2540.)
© 2007 American Heart Association, Inc.

Vascular Biology

Expression of HIF-1 in Injured Arteries Controls SDF-1–Mediated Neointima Formation in Apolipoprotein E–Deficient Mice

Ela Karshovska; Alma Zernecke; Gueler Sevilmis; Andrea Millet; Mihail Hristov; Clemens D. Cohen; Holger Schmid; Florian Krotz; Hae-Young Sohn; Volker Klauss; Christian Weber; Andreas Schober

From the Division of Cardiology (E.K., G.S., A.M., F.K., H.-Y.S., V.K., A.S.), Medizinische Poliklinik, University of Munich; Division of Nephrology (C.C., H.S.), Medizinische Poliklinik, University of Munich; and Institute of Molecular Cardiovascular Research (IMCAR) (A.Z., M.H., C.W.), University Hospital Aachen, Germany.

Correspondence Dr Andreas Schober, Division of Cardiology, Medizinische Poliklinik, University of Munich, Pettenkoferstrasse 8a, 80336 Munich, Germany. E-mail andreas.schober{at}med.uni-muenchen.de

Objective— Hypoxia-inducible factor (HIF)-1 is the regulatory subunit of a transcriptional complex, which controls the recruitment of multipotent progenitor cells and tissue repair in ischemic tissue by inducing stromal cell-derived factor (SDF)-1 expression. Because HIF-1 can be activated under normoxic conditions in smooth muscle cells (SMCs) by platelet products, we investigated the role of HIF-1 in SDF-1–mediated neointima formation after vascular injury.

Methods and Results— Wire-induced injury of the left carotid artery was performed in apolipoprotein E–deficient mice. HIF-1 expression was increased in the media as early as 1 day after injury, predominantly in SMCs. Nuclear translocation of HIF-1 and colocalization with SDF-1 was detected in neointimal cells after 2 weeks. HIF-1 mRNA expression was induced at 6 hours after injury as determined by real-time RT-PCR. Inhibition of HIF-1 expression by local application of HIF-1-siRNA reduced the neointimal area by 49% and significantly decreased the neointimal SMCs content compared with control-siRNA. HIF-1 and SDF-1 expression were clearly diminished in neointimal cells of HIF-1-siRNA treated arteries.

Conclusions— HIF-1 expression is directly involved in neointimal formation after vascular injury and mediates the upregulation of SDF-1, which may affect the stem cell–based repair of injured arteries.

We studied the role of hypoxia-inducible factor (HIF)-1 in neointima formation after vascular injury in apolipoprotein E–deficient mice. Inhibition of injury-induced HIF-1 upregulation reduced the neointimal area and stromal cell–derived factor (SDF)-1 expression. This suggests a direct contribution of HIF-1 to SDF-1–mediated neointima formation after vascular injury.

Key Words: atherosclerosis • restenosis • vascular biology • chemokines • progenitor cells • smooth muscle cells

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