title: Induction of cerebral arteriogenesis leads to early-phase expression of protease inhibitors in growing collaterals of the brain.
abstract: Cerebral arteriogenesis constitutes a promising therapeutic concept for cerebrovascular ischaemia; however, transcriptional profiles important for therapeutic target identification have not yet been investigated. This study aims at a comprehensive characterization of transcriptional and morphologic activation during early-phase collateral vessel growth in a rat model of adaptive cerebral arteriogenesis. Arteriogenesis was induced using a three-vessel occlusion (3-VO) rat model of nonischaemic cerebral hypoperfusion. Collateral tissue from growing posterior cerebral artery (PCA) and posterior communicating artery (Pcom) was selectively isolated avoiding contamination with adjacent tissue. We detected differential gene expression 24 h after 3-VO with 164 genes significantly deregulated. Expression patterns contained gene transcripts predominantly involved in proliferation, inflammation, and migration. By using scanning electron microscopy, morphologic activation of the PCA endothelium was detected. Furthermore, the PCA showed induced proliferation (PCNA staining) and CD68+ macrophage staining 24 h after 3-VO, resulting in a significant increase in diameter within 7 days after 3-VO, confirming the arteriogenic phenotype. Analysis of molecular annotations and networks associated with differentially expressed genes revealed that early-phase cerebral arteriogenesis is characterised by the expression of protease inhibitors. These results were confirmed by quantitative real-time reverse transcription-PCR, and in situ hybridisation localised the expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) and kininogen to collateral arteries, showing that TIMP-1 and kininogen might be molecular markers for early-phase cerebral arteriogenesis.
authors.affiliation: Research Group for Experimental and Clinical Arteriogenesis, Department of Internal Medicine/Cardiology, (CC13), CCR-Center for Cardiovascular Research, Charité-Universitätsmedizin Berlin, Berlin, Germany. philipp.hillmeister@charite.de
authors.forename: Philipp
authors.initials: P
authors.lastname: Hillmeister
authors.forename: Kerstin E
authors.initials: KE
authors.lastname: Lehmann
authors.forename: Anja
authors.initials: A
authors.lastname: Bondke
authors.forename: Henning
authors.initials: H
authors.lastname: Witt
authors.forename: André
authors.initials: A
authors.lastname: Duelsner
authors.forename: Clemens
authors.initials: C
authors.lastname: Gruber
authors.forename: Hans-Jörg
authors.initials: HJ
authors.lastname: Busch
authors.forename: Joachim
authors.initials: J
authors.lastname: Jankowski
authors.forename: Patricia
authors.initials: P
authors.lastname: Ruiz-Noppinger
authors.forename: Konstantin-Alexander
authors.initials: KA
authors.lastname: Hossmann
authors.forename: Ivo R
authors.initials: IR
authors.lastname: Buschmann
mesh_terms: D000818:Animals; D001157:Arterial Occlusive Diseases / Q000503:physiopathology* / Q000628:therapy*; D002545:Brain Ischemia / Q000235:genetics / Q000503:physiopathology* / Q000628:therapy; D002536:Cerebral Arteries / Q000254:growth & development / Q000502:physiology*; D002560:Cerebrovascular Circulation / Q000502:physiology*; D003097:Collateral Circulation / Q000502:physiology*; D004195:Disease Models, Animal; D017403:In Situ Hybridization; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D011480:Protease Inhibitors / Q000378:metabolism*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000685:Serum Amyloid A Protein / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D009419:Nerve Tissue Proteins; D011480:Protease Inhibitors; D000685:Serum Amyloid A Protein