Morphologic Evidence for a Preferential Storage of Tissue Plasminogen Activator (t-PA) in Perivascular Axons of the Rat Uvea

Hand, Arthur R.; Gillies, Concettina; Grunnet, Margaret L.; Cone, Robert E.; O’Rourke, James

doi:10.1006/exer.1997.0314

Cited by 14 publications

(15 citation statements)

References 28 publications

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“…Several lines of evidence have also indicated that the plasmin produced by t-PA may participate in the longterm potentiation of synaptic transmissions within the central nervous system (Mizutani et al, 1997). Immunolocalizations of t-PA within the axoplasm of ICM nerve terminals (Wang et al, 1997a) are thus consistent with a cotransport and corelease of transmitters and neuropeptides (Hendry et al, 1974).…”

Section: Discussionmentioning

confidence: 85%

“…Ultrastructural immunogold localizations of t-PA antigen in relation to individual axon terminals was then done in thin 0.1-µm sections of Lowicryl-embedded ICM tissues (Murphy et al, 1994;Hand, 1995;Wang et al, 1997a).…”

Section: T-pa Localization Studiesmentioning

confidence: 99%

“…A major technical problem in these studies has been the inability of diffuse light microscopic localizations of t-PA to discretely identify t-PA-containing cells or axon filaments within the adventitia. However, recent electron microscopic immunolocalizations have revealed a near-exclusive storage of the enzyme within the predominantely sympathetic microvascular axons of the irischoroid, most of which originate in the superior cervical sympathetic ganglion (Wang et al, 1997a). Moreover, they represent a small fraction of the total ganglion output (Stone et al, 1986;Li and Grimes, 1993), which suggests that a sympathetic neuron t-PA may be widely distributed to other vessels and tissues.…”

Section: Introductionmentioning

confidence: 99%

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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

et al. 1998

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Tissue plasminogen activator (t-PA) is expressed by hypothalamic and peripheral sympathetic neurons. The sympathetic axons that permeate artery walls have not been investigated as possible sources of intramural t-PA. The plasmin produced by such a system would locally activate both fibrinolysis and matrix metalloproteinases that regulate arterial collagen turnover. To assess this neural t-PA production, we investigated the capacity of rat cervical sympathetic ganglion neurons to synthesize and release t-PA, and the expression of the enzyme in carotid artery and the iris-choroid microvascular tissues that receive the ganglion axon distribution. Functional studies confirmed that (i) the ganglion neuron cell bodies synthesize t-PA mRNA, (ii) cultured ganglion carotid artery and iris-choroid microvascular explants predominantly release t-PA rather than urokinase, (iii) microvascular tissues release approximately 20 times more t-PA per milligram than carotid explants (which accords with the higher innervation density of small vessels), and (iv) 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 ganglion axons, the carotid adventitia that receives these axons, and the predominantly sympathetic axon terminals in the iris-choroid microvasculature. These data indicate the existence of a previously undescribed system for the delivery of neural t-PA to vessel walls. The intramural production of plasmin induced by this system represents a novel principle for the regulation of arterial matrix flexibility, especially in the media of densely innervated small arteries and resistance arterioles involved in the pathogenesis of stroke, hypertension, and vascular aging. Thus, the data suggest an important new interface between neuroscience and vascular biology that merits further exploration.

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Section: Discussionmentioning

confidence: 85%

Section: T-pa Localization Studiesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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

et al. 1998

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“…HU-VECs were incubated with anti-S1P 1 ( left ) or isotypical mouse IgG 2 b ( right ) followed by gold-particle conjugated secondary antibody as described (Mednieks et al 1987; Wang et al 1997). Note that immunogold labeling shows that S1P 1 are present both in plasma membrane ( top ) and nuclear compartments ( bottom ).…”

Section: Figuresmentioning

confidence: 99%

Ligand-induced nuclear translocation of S1P1 receptors mediates Cyr61 and CTGF transcription in endothelial cells

Estrada

Wang

Jala

et al. 2008

Histochem Cell Biol

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Sphingosine-1-phosphate (S1P) receptor subtype 1 (S1P 1 ), a G-protein coupled receptor (GPCR), regulates many biological activities of endothelial cells (ECs). In this report, we show that S1P 1 receptors are present in the nuclei of ECs by using various biochemical and microscopic techniques such as cellular fractionation, immunogold labeling, and confocal microscopic analysis. Live cell imaging showed that plasma membrane S1P 1 receptors are rapidly internalized and subsequently translocated to nuclear compartment upon S1P stimulation. Utilizing membrane biotinylation technique further supports the notion that nuclear S1P 1 receptors were internalized from plasma membrane S1P 1 after ligand treatment. Moreover, nuclear S1P 1 is able to regulate the transcription of Cyr61 and CTGF, two growth factors functionally important in the regulation of vasculature. Collectively, these data suggest a novel S1P-S1P 1 signaling axis present in the nuclear compartment of endothelial cells, which may regulate biological responses of endothelium.

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“…The peripheral SNS axons that densely innervate small resistance arteries and arterioles in rats were recently shown to store large amounts of plasminproducing t-PA in secretory vesicles, similar to those that release norepinephrine onto the smooth muscle layer (Wang et al 1997, Jiang et al 2000. (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

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

Zou

Jiang

Sharafeih

et al. 2005

Stress

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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.

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Morphologic Evidence for a Preferential Storage of Tissue Plasminogen Activator (t-PA) in Perivascular Axons of the Rat Uvea

Cited by 14 publications

References 28 publications

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

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

Ligand-induced nuclear translocation of S1P1 receptors mediates Cyr61 and CTGF transcription in endothelial cells

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

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