Stimulated release of tissue plasminogen activator from artery wall sympathetic nerves: Implications for stress-associated wall damage

Abstract

Recurrent stress is clinically associated with early onset hypertension and coronary artery disease. A mechanism linking emotion to pathogenic remodeling of the artery wall has not been identified. Stress stimulates acute regulated release of tissue plasminogen activator (t-PA) into the circulation, which is presently attributed to the vascular endothelium. Sympathetic neurons also synthesize t-PA and axonally transport it to the arterial smooth muscle. Unlike release by the endothelium, a stress-stimulated sympathetic discharge would potentially accelerate degradation of the wall matrix by plasmin. To assess whether sympathetic axons are the principal source of acute stress-induced arterial release of t-PA, we compared the output from small densely innervated and large sparsely innervated isolated artery segments before and after sympathetic stimulation, and after ablations. Following phenylephrine infusion densely-innervated microvessels in uveal eyecups were released over 60-fold greater amounts of active t-PA per milligram than the sparsely innervated aorta; and ten-fold more than carotid artery segments. Mesenteric artery release was 4.8-fold greater than release by the carotid artery. In vivo, uveal release of t-PA increased more than three-fold within one minute following superior cervical sympathetic ganglion electrical stimulation, and after phenylephrine, or nicotine infusions of the anterior chamber. Circulating levels of t-PA fell 70% following chemical sympathectomy. We propose that sympathetic nerves are the primary source of stress-induced release of t-PA into and from the densely innervated resistance arteries and arterioles, where dysregulated plasmin-induced proteolysis could damage the wall matrix.

Different cardiac tissue plasminogen activator release patterns by local stimulation of the endothelium and sympathetic nerves in pigs

“…One hypothesis might be that the first peak represents tPA co-released with NE from sympathetic nerve endings [16,17,27,28], whereas the second peak represents a NE-mediated tPA release from endothelial cells. This is new information and we can only speculate on the mechanisms involved.…”

Acute mental stress and hemostasis: When physiology becomes vascular harm

“…Catecholamines also stimulate hepatic release of FVIII and affect hepatic clearance of t-PA and likely D-dimer [2]. Sympathetic nerves in artery walls are a further important source of acute-stress induced increase in circulating t-PA [19]. Catecholamines also activate platelets through stimulation of alpha2-adrenergic receptors [18].…”

Inhibition of carboxypeptidase U (TAFIa) activity improves rt-PA induced thrombolysis in a dog model of coronary artery thrombosis

“…One possibility is that t-PA released from the sympathetic terminals system itself contributes to the observed response. O'Rourke and co-workers have shown that sympathetic neurons can synthesise and release t-PA [162,163]. However, whether t-PA derived from sympathetic neurons actually reaches the blood stream remains to be determined.…”