INCREASED SECRETION OF GELATINASE-A AND GELATINASE-B FROM THE AORTAS OF CHOLESTEROL-FED RABBITS - RELATIONSHIP TO LESION SEVERITY

Basement membrane degrading metalloproteinases (gelatinases) have been implicated in the regulation of vascular smooth muscle cell migration and proliferation in culture and during neointima formation in vivo. We compared the expression and activation of gelatinases A and B in ex plants derived from the arch, mid and distal portions of thoracic aort as of normal rabbits and those given a 1% cholesterol-containing diet for 8 weeks. Neointimal/medial ratio was less than 0.01 in normal rabb its but was significantly increased by cholesterol feeding in the arch (1.08 +/- 0.26), mid (0.75 +/- 0.28) and distal (0.32 +/- 0.12); port ions of the aorta (mean +/- S.E.M., n = 6), and to a significantly (P < 0.05) greater extent in the arch and mid than distal portions. Secre tion of gelatinase B measured by densitometric scanning of zymograms w as undetectable from normal aortas, but was significantly increased by cholesterol feeding in the arch (0.16 +/- 0.06), mid (0.26 +/- 0.08) and distal (0.11 +/- 0.05) portions (optical density units, n = 6, eac h P < 0.05 versus normal diet). The increase in gelatinase B expressio n was localised by in situ hybridisation to neointimal vascular smooth muscle cells, macrophages and endothelial cells. Secretion of pro-gel atinase A was detected from normal aortas; it was increased by cholest erol feeding from the arch (4.0 versus 2.8, P < 0.05) and mid (3.6 ver sus 2.8, P < 0.05) but not distal portions of the aorta (1.8 versus 1. 2, n.s.). Similar results were obtained for active gelatinase A secret ion from the arch (0.50 versus 0.28, P < 0.05) and mid (0.47 versus 0. 23, P < 0.05) but not distal portions (0.19 versus 0.20, n.s.). Increa ses in pro- and active gelatinase A secretion therefore paralleled the severity of atheroma formation. The results imply that increased base ment membrane turnover mediated by gelatinases occurs during cholester ol induced atherosclerosis formation. (C) 1997 Elsevier Science Irelan d Ltd.