In vitro and in vivo effects of tPA and PAI-1 on blood vessel tone

Nassar, Taher; Akkawi, Sa’ed; Shina, Ahuva; Haj‐Yehia, Abdullah; Bdeir, Khalil; Tarshis, Mark; Heyman, Samuel N.; Higazi, Abd Al‐Roof

doi:10.1182/blood-2003-05-1685

Cited by 98 publications

(127 citation statements)

References 29 publications

Supporting

Mentioning

119

Contrasting

Order By: Relevance

“…This outcome suggests that the vasorelaxation induced by high concentrations of uPA is mediated through a process that does not require LRP-1 or a related family member. This is similar to our previous finding that the vasoactive effect induced by high concentrations of tPA (20 nM) is independent of LRP (30).…”

Section: Role Of Lrp and Upa Catalytic Activitysupporting

confidence: 82%

See 1 more Smart Citation

Urokinase Plasminogen Activator Regulates Pulmonary Arterial Contractility and Vascular Permeability in Mice

Nassar

Yarovoi

Fanne

et al. 2011

Am J Respir Cell Mol Biol

Self Cite

View full text Add to dashboard Cite

The concentration of urokinase plasminogen activator (uPA) is elevated in pathological settings such as acute lung injury, where pulmonary arterial contractility and permeability are disrupted. uPA limits the accretion of fibrin after injury. Here we investigated whether uPA also regulates pulmonary arterial contractility and permeability. Contractility was measured using isolated pulmonary arterial rings. Pulmonary blood flow was measured in vivo by Doppler and pulmonary vascular permeability, according to the extravasation of Evans blue. Our data show that uPA regulates the in vitro pulmonary arterial contractility induced by phenylephrine in a dose-dependent manner through two receptor-dependent pathways, and regulates vascular contractility and permeability in vivo. Physiological concentrations of uPA (<1 nM) stimulate the contractility of pulmonary arterial rings induced by phenylephrine through the low-density lipoprotein receptor-related protein receptor. The procontractile effect of uPA is independent of its catalytic activity. At pathophysiological concentrations, uPA (20 nM) inhibits contractility and increases vascular permeability. The inhibition of vascular contractility and increase of vascular permeability is mediated through a two-step process that involves docking to N-methyl-Daspartate receptor-1 (NMDA-R1) on pulmonary vascular smooth muscle cells, and requires catalytic activity. Peptides that specifically inhibit the docking of uPA to NMDA-R, or the uPA variant with a mutated receptor docking site, abolished both the effects of uPA on vascular contractility and permeability, without affecting its catalytic activity. These data show that uPA, at concentrations found under pathological conditions, reduces pulmonary arterial contractility and increases permeability though the activation of NMDA-R1. The selective inhibition of NMDAR-1 activation by uPA can be accomplished without a loss of fibrinolytic activity.

show abstract

Section: Role Of Lrp and Upa Catalytic Activitysupporting

confidence: 82%

“…We previously observed that the stimulatory, but not inhibitory, effects of tPA on the contraction of isolated aortic rings were LRP-dependent (30). Therefore, we examined the involvement of this receptor in uPA-induced alterations in pulmonary arterial contractility.…”

Section: Role Of Lrp and Upa Catalytic Activitymentioning

confidence: 99%

Urokinase Plasminogen Activator Regulates Pulmonary Arterial Contractility and Vascular Permeability in Mice

Nassar

Yarovoi

Fanne

et al. 2011

Am J Respir Cell Mol Biol

Self Cite

View full text Add to dashboard Cite

show abstract

“…MK-801 blocks the neurotoxic effects of tPA by blocking the receptor, thereby inhibiting calcium overload. Recently, it has been shown that tPA can have complex vasoactive roles in brain; at low 1 nM concentrations tPA inhibits phenylephrine-induced vasoconstriction, whereas at high 20 nM concentrations tPA augmented phenylephrine's effects on vessel tone (Nasser et al, 2004).…”

Section: Tpa Neurotoxicity Via Nmda Receptorsmentioning

confidence: 99%

The Neurotoxicity of Tissue Plasminogen Activator?

Kaur

Zhao

Klein

et al. 2004

J Cereb Blood Flow Metab

240

185

View full text Add to dashboard Cite

Abstract:Tissue plasminogen activator (tPA), a fibrin specific activator for the conversion of plasminogen to plasmin, stimulates thrombolysis and rescues ischemic brain by restoring blood flow. However, emerging data suggests that under some conditions, both tPA and plasmin, which are broad spectrum protease enzymes, are potentially neurotoxic if they reach the extracellular space. Animal models suggest that in severe ischemia with injury to the blood brain barrier (BBB) there is injury attributed to the protease effects of this exogenous tPA. Besides clot lysis per se, tPA may have pleiotropic actions in the brain, including direct vasoactivity, cleaveage of the N-methyl-Daspartate (NMDA) NR1 subunit, amplification of intracellular Ca ++ conductance, and activation of other extracellular proteases from the matrix metalloproteinase (MMP) family, e.g. MMP-9. These effects may increase excitotoxicity, further damage the BBB, and worsen edema and cerebral hemorrhage. If tPA is effective and reverses ischemia promptly, the BBB remains intact and exogenous tPA remains within the vascular space. If tPA is ineffective and ischemia is prolonged, there is the risk that exogenous tPA will injure both the neurovascular unit and the brain. Methods of neuroprotection, which prevent tPA toxicity or additional mechanical means to open cerebral vessels, are now needed.

show abstract

“…22 WT-tPA (50 nM) or WT-uPA (5 nM) was incubated with plasminogen (500 nM) and the chromogenic substrate of plasmin S-2251 (Innovative Research, Novi, MI) (100 mM) alone or in the presence of tPA-S 481 A (100 nM) or tranexamic acid (1 mM). Generation of plasmin was assessed by change in optical density (OD) at 405 nm.…”

Section: Chromogenic Assay Of Plasminogen Activationmentioning

confidence: 99%

“…Plasminogen activators (PAs) play important roles in neurotransmission, [17][18][19] postinjury neuronal apoptosis, 20,21 and regulation of cerebrovascular reactivity, 15,16,22 but their contributions to ICH have received less attention. We hypothesized that a rapid, protracted, and striking increase in the local concentration of endogenous PAs is primarily responsible for exuberant local fibrinolysis at sites of trauma, leading to premature clot lysis and expansion of ICH.…”

Section: Introductionmentioning

confidence: 99%