Protease nexin-1 (PN-1) is a potent inhibitor of serine proteases, such as thrombin and plasminogen activators, which is secreted into the extracellular space. Since PN-1 is induced following lesion of the sciatic nerve, the effect of substances known to accumulate at the site of injury was examined in primary cultures of Schwann cells. Among the cytokines, growth factors, mitogens, neurotrophins, and neuroactive peptides analyzed, only angiotensin II (Ang II), calcitonin gene- related peptide (CGRP), and vasoactive intestinal peptide (VIP) were found to regulate the expression of PN-1 on Schwann cells. While Ang II and CGRP caused downregulation, VIP acted as a positive modulator of PN- 1. Displacement of Ang II binding using the selective ligands losartan and CGP 42112 led to a severalfold increase of PN-1 protein and mRNA over basal levels, indicating that the observed effect was mediated by specific binding sites. Indeed, the presence of AT1 and AT2 angiotensin receptor subtypes was demonstrated in cultured Schwann cells as well as in the rat sciatic nerve. Moreover, the detection of angiotensinogen- and renin-mRNA in these cultures suggested an endogenous production of Ang II. This data identified one of the mechanisms regulating PN-1 synthesis. Altogether our results indicate that neuropeptides can differentially control the proteolytic activity of the microenvironment, providing new aspects of neuron-glia interactions in the intact tissue and following nerve injury.