title: PECAM-1-targeted micron-sized particles of iron oxide as MRI contrast agent for detection of vascular remodeling after cerebral ischemia.
abstract: An increasing amount of studies have provided evidence for vascular remodeling, for example, angiogenesis, after cerebral ischemia, which may play a significant role in post-stroke brain plasticity and recovery. Molecular imaging can provide unique in vivo whole-brain information on alterations in the expression of specific endothelial markers. A possible target for molecular magnetic resonance imaging (MRI) of post-stroke (neo)vascularization is platelet endothelial cell adhesion molecule-1 (PECAM-1). Here we describe significantly increased PECAM-1 mRNA levels in ipsilesional brain tissue at 6 h, 24 h and 3 days after transient middle cerebral artery occlusion in mice, and elevated PECAM-1 staining throughout the lesion at 3, 7 and 21 days post-stroke. The potential of micron-sized particles of iron oxide (MPIO) conjugated with PECAM-1-targeted antibodies, that is, αPECAM-1-MPIO, to expose stroke-induced PECAM-1 upregulation with molecular MRI was assessed. In vitro studies demonstrated that PECAM-1-expressing brain endothelial cells could be effectively labeled with αPECAM-1-MPIO, giving rise to a fourfold increase in MRI relaxation rate R2. Injection of near-infrared fluorescent dye-labeled αPECAM-1 showed target specificity and dose efficiency of the antibody for detection of brain endothelial cells at 3 days post-stroke. However, in vivo molecular MRI at 3 and 7 days after stroke revealed no αPECAM-1-MPIO-based contrast enhancement, which was corroborated by the absence of αPECAM-1-MPIO in post mortem brain tissue. This indicates that this molecular MRI approach, which has been proven successful for in vivo detection of other types of cell adhesion molecules, is not invariably effective for MRI-based assessment of stroke-induced alterations in expression of cerebrovascular markers.
authors.affiliation: Biomedical MR Imaging and Spectroscopy Group, Image Sciences Institute, University Medical Center Utrecht, Yalelaan 2, 3584 CM Utrecht, The Netherlands. lisette@invivonmr.uu.nl
authors.forename: Lisette H
authors.initials: LH
authors.lastname: Deddens
authors.forename: Geralda A F
authors.initials: GA
authors.lastname: van Tilborg
authors.forename: Annette
authors.initials: A
authors.lastname: van der Toorn
authors.forename: Helga E
authors.initials: HE
authors.lastname: de Vries
authors.forename: Rick M
authors.initials: RM
authors.lastname: Dijkhuizen
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000473:pathology; D003287:Contrast Media / Q000008:administration & dosage* / Q000737:chemistry; D005290:Ferric Compounds / Q000008:administration & dosage* / Q000737:chemistry; D005786:Gene Expression Regulation; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology; D018810:Magnetic Resonance Angiography; D051379:Mice; D057054:Molecular Imaging; D018919:Neovascularization, Physiologic; D010316:Particle Size; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D011859:Radiography; D020521:Stroke / Q000000981:diagnostic imaging* / Q000473:pathology
chemical_list: D003287:Contrast Media; D005290:Ferric Compounds; D019408:Platelet Endothelial Cell Adhesion Molecule-1; C000499:ferric oxide