FUNCTIONAL AND MORPHOLOGIC EVIDENCE OF THE PRESENCE OF TISSUE-PLASMINOGEN ACTIVATOR IN VASCULAR NERVES - IMPLICATIONS FOR A NEUROLOGIC CONTROL OF VESSEL WALL FIBRINOLYSIS AND RIGIDITY

Tissue plasminogen activator (t-PA) is expressed by hypothalamic and p eripheral sympathetic neurons. The sympathetic axons that permeate art ery walls have not been investigated as possible sources of intramural t-PA. The plasmin produced by such a system would locally activate bo th fibrinolysis and matrix metalloproteinases that regulate arterial c ollagen turnover. To assess this neural t-PA production, we investigat ed the capacity of rat cervical sympathetic ganglion neurons to synthe size and release t-PA, and the expression of the enzyme in carotid art ery and the iris-choroid microvascular tissues that receive the gangli on axon distribution. Functional studies confirmed that (i) the gangli on neuron cell bodies synthesize t-PA mRNA, (ii) cultured ganglion car otid artery and iris-choroid microvascular explants predominantly rele ase t-PA rather than urokinase, (iii) microvascular tissues release si milar to 20 times more t-PA per milligram than carotid explants (which accords with the higher innervation density of small vessels), and (i v) removal of the endothelium did not cause major reductions in the t- PA release from carotid and microvascular explants. Immunolocalization studies then confirmed a strong expression of the enzyme within the g anglion axons, the carotid adventitia that receives these axons, and t he predominantly sympathetic axon terminals in the iris-choroid microv asculature. These data indicate the existence of a previously undescri bed system for the delivery of neural t-PA to vessel walls. The intram ural production of plasmin induced by this system represents a novel p rinciple for the regulation of arterial matrix flexibility, especially in the media of densely innervated small arteries and resistance arte rioles involved in the pathogenesis of stroke, hypertension, and vascu lar aging. Thus, the data suggest an important new interface between n euroscience and vascular biology that merits further exploration. (C) 1998 Wiley-Liss, Inc.