Molecular anatomy of an intracranial aneurysm: coordinated expression of genes involved in wound healing and tissue remodeling.
OBJECTIVE
Approximately 6% of human beings harbor an unruptured intracranial aneurysm. Each year in the United States, >30 000 people suffer a ruptured intracranial aneurysm, resulting in subarachnoid hemorrhage. Despite the high incidence and catastrophic consequences of a ruptured intracranial aneurysm and the fact that there is considerable evidence that predisposition to intracranial aneurysm has a strong genetic component, very little is understood with regard to the pathology and pathogenesis of this disease.


METHODS
To begin characterizing the molecular pathology of intracranial aneurysm, we used a global gene expression analysis approach (SAGE-Lite) in combination with a novel data-mining approach to perform a high-resolution transcript analysis of a single intracranial aneurysm, obtained from a 3-year-old girl.


RESULTS
SAGE-Lite provides a detailed molecular snapshot of a single intracranial aneurysm. These data suggest that, at least in this specific case, aneurysmal dilation results in a highly dynamic cellular environment in which extensive wound healing and tissue/extracellular matrix remodeling are taking place. Specifically, we observed significant overexpression of genes encoding extracellular matrix components (eg, COL3A1, COL1A1, COL1A2, COL6A1, COL6A2, elastin) and genes involved in extracellular matrix turnover (TIMP-3, OSF-2), cell adhesion and antiadhesion (SPARC, hevin), cytokinesis (PNUTL2), and cell migration (tetraspanin-5).


CONCLUSIONS
Although these are preliminary data, representing analysis of only one individual, we present a unique first insight into the molecular basis of aneurysmal disease and define numerous candidate markers for future biochemical, physiological, and genetic studies of intracranial aneurysm. Products of these genes will be the focus of future studies in wider sample sets.
Peters
D G
DG
Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, PA, USA. dpeters@helix.hgen.pitt.edu
Kassam
A B
AB
Feingold
E
E
Heidrich-O'Hare
E
E
Yonas
H
H
Ferrell
R E
RE
Brufsky
A
A
D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002533:Cerebral Angiography; D002675:Child, Preschool; D020224:Expressed Sequence Tags; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling / Q000379:methods; D005787:Gene Frequency; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000473:pathology; D002532:Intracranial Aneurysm / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D020768:Middle Cerebral Artery / Q000378:metabolism / Q000473:pathology*; D015676:Osteonectin / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012038:Regeneration / Q000235:genetics*; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics / Q000378:metabolism; D014945:Wound Healing / Q000235:genetics*
D002135:Calcium-Binding Proteins; D015815:Cell Adhesion Molecules; D018797:Cell Cycle Proteins; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; D008565:Membrane Proteins; D015676:Osteonectin; C512835:POSTN protein, human; D012333:RNA, Messenger; C503126:SPARCL1 protein, human; C503127:Sparcl1 protein, mouse; D019717:Tissue Inhibitor of Metalloproteinase-3