ROLE OF EXTRACELLULAR-MATRIX IN EXPERIMENTAL VASOSPASM - INHIBITORY EFFECT OF ANTISENSE OLIGONUCLEOTIDE ON COLLAGEN INDUCTION

Background and Purpose Although it has been suggested that collagen pl ays a role in the pathogenesis of cerebral vasospasm after subarachnoi d hemorrhage, there has been no constructive research to prove it dire ctly. In this study we stopped the transcription of the procollagen ty pe I gene by introducing antisense oligonucleotides for its mRNA in a rat femoral artery model of vasospasm induced by blood and assayed the changes in the vasoconstrictive activity of the vessel and expression of the procollagen mRNA. Methods We applied antisense, sense, or miss ense oligonucleotides, located at the carboxyl propeptide region for a lpha 1(I) procollagen mRNA, onto the femoral artery in a rat femoral a rtery model of vasospasm. The diameter of the artery was measured by a ngiography. The transcription level of the procollagen gene in the art erial tissue was assayed by use of reverse transcription-polymerase ch ain reaction. Morphological change in the artery was observed with ald ehyde-fuchsin-Masson-Goldner staining. Results In the model, when the artery was exposed to antisense oligonucleotides in pluronic gel for 5 days to prevent arterial contraction, the contraction was inhibited a t a significant level (76.0% +/- 5.6) when compared with that in contr ol experiments using sense oligonucleotides (64.0% +/- 2.4), missense oligonucleotides (63.5% +/- 3.5), or gel alone (62.1% +/- 5.8). The ap plication of antisense oligonucleotide resulted in a marked decrease i n alpha 1(I) procollagen mRNA expression as determined by polymerase c hain reaction, indicating that the collagen reduction by antisense oli gonucleotides occurred at the transcription level. Histological staini ng suggested that collagen accumulation at the site in the artery wher e antisense oligonucleotide had been administered was indeed less than that in the control artery. Conclusions The results indicate that the induction of procollagen type I could cause pathogenesis of the arter ial contraction induced bq blood in a rat femoral vasospasm model.