GELATINASE ACTIVITY AND THE OCCURRENCE OF CEREBRAL ANEURYSMS

Background and Purpose Cerebral aneurysms are associated with decrease d arterial collagen content; however, whether this deficiency results from impaired collagen synthesis or enhanced collagen degradation is u nknown. This study tested the hypothesis that enhanced collagen degrad ation, not impaired collagen synthesis, is associated with the occurre nce of cerebral aneurysms. Methods Cultured skin fibroblasts and serum samples were studied in patients with angiographic evidence of aneury sm (n=31) and control subjects (n=14). Transcription of the type III c ollagen gene was assessed with the use of Northern blots prepared from RNA harvested from confluent cultured fibroblasts. Translation of typ e III collagen was assessed by Western blot analysis of proteins produ ced by cultured skin fibroblasts. Collagen metabolism was assessed by radioimmunoassay for type I (PICP) and type III (PIIINP) procollagen p eptides in conditioned tissue culture media and serum. We assessed col lagen degradation in serum and conditioned tissue culture media by eva luating gelatinase activity using quantitative zymography. Results Typ e III collagen synthesis was the same in aneurysm and control patients . Neither the molecular weight nor the relative amount of type III col lagen mRNA differed between aneurysm and control patient fibroblasts. Western blot analysis revealed no difference in the relative amount or molecular weight of procollagen III synthesized by aneurysm and contr ol cells. Aneurysm patients had a threefold increase in native serum g elatinase activity compared with control subjects (P=.004). This incre ase occurred along with serum evidence of increased collagen metabolis m. Serum levels of PICP (P=.03) and PIIINP (P=.02) were decreased in a neurysm patients. Elevated serum gelatinase activity and altered colla gen metabolism could not be explained by enhanced secretion of gelatin ase by cultured fibroblasts or altered net collagen synthesis by fibro blasts. High serum gelatinase activity was more common in men than in women (P=.04). Conclusions These findings are consistent with the hypo thesis that accelerated enzymatic degradation of collagens and other s tructural proteins compromises the mechanical integrity of the cerebra l vessel wall and leads to conditions that favor aneurysm formation.