We previously reported that serine elastase activity is induced in cultured porcine pulmonary artery (PA) smooth muscle cells (SMC) following serum stimulation by a mechanism involving adhesion of elastin to an elastin binding protein and tyrosine kinase activity. The present study demonstrates that a PA endothelial cell factor also promotes a fourfold increase in elastin adhesion to PA SMC and a twofold increase in serine elastase activity. The mechanism involves tethering of the factor to SMC, since [³H]‐elastin pre‐incubated with serum or endothelial cell (EC)‐conditioned medium or SMC pre‐treated with serum accelerates binding of elastin and tyrosine‐kinase related elastase activity. The serum factor appears to interact with integrins as elastase induction is partially inhibited by RGD peptides. The elastase‐inducing properties of serum could not, however, be attributed to several RGD‐containing proteins. While a 120 kD fibronectin fragment partially reproduced the effect, it was not found in the serum fraction containing elastase‐inducing activity. Instead, a 27 kD serum protein was enriched by elastin affinity chromatography, identified as apolipoprotein (Apo) A1 by microsequence analysis, and found to have about 50% of the elastase‐inducing activity of serum. Elastase induction is inhibited by actinomycin and cycloheximide, suggesting a requirement for mRNA transcription and protein synthesis. Our results suggest a novel cell‐extracellular matrix interaction whereby a soluble factor, in this case a lipoprotein, binds and tethers a matrix component to the cell surface and induces tyrosine kinase‐dependent transcription of mRNA culminating in substrate proteolysis. J. Cell. Physiol. 174:78–89, 1998. © 1998 Wiley‐Liss, Inc.