Sympathectomy decreases and adrenergic stimulation increases the release of tissue plasminogen activator (t-PA) from blood vessels: Functional evidence for a neurologic regulation of plasmin production within vessel walls and other tissue matrices

Abstract

Our recent morphologic studies indicated that peripheral nervous system (PNS) adrenergic neurons synthesize, transport, and store the serene protease, tissue plasminogen activator (t-PA) in axon terminals, many of which innervate vessel walls. Sympathoadrenal stimulation induces a surge of t-PA from vessel walls into the blood. The vascular endothelium, which constitutively secretes t-PA into blood also has long been widely assumed to be the principal source of this stress-induced release, but has not been verified as such. A neurologically regulated release from adrenergic stores could thus augment the known constitutive endothelial release. To functionally test this possibility, we quantitated the effects of guanethidine-induced systemic sympathectomy on the basal and stimulated release of t-PA from isolated vessel explants in superfused organ cultures. Moment-to-moment changes in the release rate were plotted from serial assays of the t-PA free activity. The effects of endothelial and adventitial nerve plexus ablations were also tested. Sympathectomy induced 30-50% reductions in t-PA release from both arterial and microvascular explants. An acute release induced by alpha-1 adrenergic receptor stimulations was also strongly suppressed, as were basal levels of the circulating enzyme in vivo. Adventitial and endothelial ablations from normal large vessel explants produced greater reductions than small vessel endothelial ablations. Ganglion electrical stimulation also induced an acute microvascular release in vivo. These and past morphologic findings indicate a physiological infusion of t-PA into the vessel walls, blood, and other innervated matrices by sympathetic neurons.

Amyloid β-Protein Stimulates the Expression of Urokinase-type Plasminogen Activator (uPA) and Its Receptor (uPAR) in Human Cerebrovascular Smooth Muscle Cells

“…Together, these findings suggest that uPA/uPAR expression and subsequent plasminogen activation may initially be increased as a mechanism to protect the vulnerable HCSM cells from the downstream pathologic consequences resulting from pathogenic A␤ deposition. Even though uPA was the only plasminogen activator detected in cultured HCSM cells tPA is likely present in cerebral vessels as well through production by the endothelium (58,59). The present results are very similar to the recent findings of Tucker et al (30,32,60) which showed that A␤ stimulated the expression of tPA and uPA in cultured primary neurons, and in the presence of plasminogen, led to degradation of A␤ and protection from its neurotoxic effects.…”

Modulation of Sympathetic Activity by Tissue Plasminogen Activator Is Independent of Plasminogen and Urokinase

“…Prominent t-PA immunostaining is present in sympathetic axons of small arteries, arterioles, and vasa vasorum (Lochner et al, 1998;O'Rourke et al, 2005). Evidence for an axonal source of t-PA activity includes: 1) a decreased blood fibrinolytic activity following guanethidine sympathectomy (Peng et al, 1999), 2) an increased regional blood t-PA activity during in vivo electrical stimulations of sympathetic nerves (Jern et al, 1994;Björk-man et al, 2003), 3) much slower t-PA-releasing kinetics from resting cultured endothelial cells than from sympathetic neurons, and 4) very prominent arteriolar t-PA immunostaining in striated muscle arterioles, but not in venules (Huber et al, 2002). In addition, u-PA has been found to be present within the sympathetic nervous system (Pittman et al, 1989).…”

“…In addition to its endothelial source, t-PA is synthesized in neural tissue (Peng et al, 1999;Jiang et al, 2002;O'Rourke et al, 2005). A recent report using a transgenic mouse model demonstrated a highly confined expression of t-PA in embryonic cells derived from the neural crest, with most prominent staining in the adrenal medulla and cervical ganglia, the sympathetic chain, axons within the myocardium, and the adventitial surface of several arteries (Hao et al, 2006).…”

The anti-fibrinolytic SERPIN, plasminogen activator inhibitor 1 (PAI-1), is targeted to and released from catecholamine storage vesicles

“…Previous studies have demonstrated that sympathoadrenal and sympathoneural tissues may represent substantial sources contributing to changes in plasma t-PA concentrations. 41,42 Further studies will be required to determine what conditions and factors may alter local PAI-1/t-PA balance in these cells.In addition to providing a potential source of circulating PAI-1, the presence of PAI-1 within catecholamine storage vesicles and the release of PAI-1 from these organelles have important implications for neuroendocrine function. Previously we have provided evidence for the presence of a local, chromaffin cell plasminogen activation system, which includes secretory vesicle t-PA, and high affinity cell surface receptors for plasminogen and t-PA, to promote plasminogen activation at the cell surface.…”

“…Previous studies have demonstrated that sympathoadrenal and sympathoneural tissues may represent substantial sources contributing to changes in plasma t-PA concentrations. 41,42 Further studies will be required to determine what conditions and factors may alter local PAI-1/t-PA balance in these cells.…”