Gene expression after crush injury of human saphenous vein: using microarrays to define the transcriptional profile.
BACKGROUND
Vein graft stenosis is believed to be the pathophysiologic response of vascular tissue to injury and is the major cause of vein graft failure. Therapeutic interventions might improve with knowledge of the physiologic pathways involved in the hyperplastic response to vascular injury. In this study, our purpose was to identify induced, early pathways that might be important in the human response to vascular injury.


METHODS
Human saphenous vein from 7 patients was organ cultured or crush injured and cultured for 48 or 72 hours after harvest. Gene expression was determined for syngeneic veins at harvest and at the experimental time points and compared to determine which genes were induced or repressed. Expressed genes (the transcriptional profile) were then assigned to functional physiologic classes.


RESULTS
At 72 hours, in both organ-cultured and crush-injured vein, the gene for the Wnt ligand protein (WNT5A) was induced. At 48 hours in the organ-cultured vein only, the gene for the Frizzled protein (FZD2), a subunit of the Wnt receptor complex, was repressed. At 72 hours in injured vein only, the gene for the product of Wnt signaling (WISP1) was induced; the gene for the Wnt-binding, soluble Frizzled-related protein (FRZB) was repressed; and the gene for Dickkopf (DKK1) protein, which binds to the low density lipoprotein receptor-related protein subunit of the Wnt receptor complex, was induced.


CONCLUSIONS
Early induction of WNT5A, coupled with the coordinated induction and repression of genes that modulate the Wnt signaling pathway, led to the early, selective induction of WISP1 and no other Wnt-inducible genes. This early, selective expression of a limited gene set might characterize the human vascular response to injury, and could enable development of therapies to treat the clinical sequelae of this response.
Department of Surgery, Morristown Memorial Hospital, Atlantic Health System, Morristown, NJ 07962-1956, USA.
Ray M
RM
Price
Nirman
N
Tulsyan
James J
JJ
Dermody
Marvin
M
Schwalb
Patricia
P
Soteropoulos
John J
JJ
Castronuovo
D055511:CCN Intercellular Signaling Proteins; D002352:Carrier Proteins / Q000378:metabolism*; D051157:Frizzled Receptors; D020869:Gene Expression Profiling; D006801:Humans; D006965:Hyperplasia / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D020411:Oligonucleotide Array Sequence Analysis; D015513:Oncogene Proteins / Q000378:metabolism*; D009924:Organ Culture Techniques; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled; D017981:Receptors, Neurotransmitter / Q000378:metabolism*; D012501:Saphenous Vein / Q000293:injuries* / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic / Q000502:physiology*; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D014945:Wound Healing / Q000235:genetics*
D055511:CCN Intercellular Signaling Proteins; C116396:CCN4 protein, human; C492066:CCN4 protein, rat; D002352:Carrier Proteins; C501126:DKK1 protein, human; C489742:FZD2 protein, human; D051157:Frizzled Receptors; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D017981:Receptors, Neurotransmitter; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein