|
|
Blood, 1 February 2004, Vol. 103, No. 3, pp. 897-902.
Prepublished online as a Blood First Edition Paper on September 25, 2003; DOI 10.1182/blood-2003-05-1685.
 Previous Article | Table of Contents | Next Article 
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
In vitro and in vivo effects of tPA and PAI-1 on blood vessel tone
Taher Nassar,
Sa'ed Akkawi,
Ahuva Shina,
Abdullah Haj-Yehia,
Khalil Bdeir,
Mark Tarshis,
Samuel N. Heyman, and
Abd Al-Roof Higazi
From the Departments of Clinical Biochemistry and Medicine, Hadassah Hospital, Mt Scopus, Israel; Interdepartmental Unit and School of Pharmacy, Hadassah University Hospital and Hebrew University-Hadassah Medical School, Jerusalem, Israel; and the Departments of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia.
Tissue type plasminogen activator (tPA) is a key enzyme in the fibrinolytic cascade. In this paper we report that tPA contains 2 independent epitopes that exert opposite effects on blood vessel tone. Low concentrations of tPA (1 nM) inhibit the phenylephrine (PE)–induced contraction of isolated aorta rings. In contrast, higher concentrations (20 nM) stimulate the contractile effect of PE. The 2 putative vasoactive epitopes of tPA are regulated by the plasminogen activator inhibitor-1 (PAI-1) and by a PAI-1–derived hexapeptide that binds tPA. TNK-tPA, a tPA variant in which the PAI-1 docking site has been mutated, stimulates PE-induced vasoconstriction at all concentrations used. The stimulatory, but not the inhibitory, effect of tPA on the contraction of isolated aorta rings was abolished by anti–low-density lipoprotein receptor–related protein/ 2-macroglobulin receptor (LRP) antibodies. Administering tPA or TNK-tPA to rats regulates blood pressure and cerebral vascular resistance in a dose-dependent mode. In other in vivo experiments we found that the vasopressor effect of PE is more pronounced in tPA knockout than in wild-type mice. Our findings draw attention to a novel role of tPA and PAI-1 in the regulation of blood vessel tone that may affect the course of ischemic diseases.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
K. Hu, L. Lin, X. Tan, J. Yang, G. Bu, W. M. Mars, and Y. Liu
tPA Protects Renal Interstitial Fibroblasts and Myofibroblasts from Apoptosis
J. Am. Soc. Nephrol.,
March 1, 2008;
19(3):
503 - 514.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Dagues, V. Pawlowski, C. Sobry, G. Hanton, F. Borde, S. Soler, J.-L. Freslon, and S. Chevalier
Investigation of the Molecular Mechanisms Preceding PDE4 Inhibitor-Induced Vasculopathy in Rats: Tissue Inhibitor of Metalloproteinase 1, a Potential Predictive Biomarker
Toxicol. Sci.,
November 1, 2007;
100(1):
238 - 247.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Lopez-Bermejo, B. Chico-Julia, A. Castro, M. Recasens, E. Esteve, J. Biarnes, R. Casamitjana, W. Ricart, and J.-M. Fernandez-Real
Alpha Defensins 1, 2, and 3: Potential Roles in Dyslipidemia and Vascular Dysfunction in Humans
Arterioscler. Thromb. Vasc. Biol.,
May 1, 2007;
27(5):
1166 - 1171.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Polavarapu, M. C. Gongora, H. Yi, S. Ranganthan, D. A. Lawrence, D. Strickland, and M. Yepes
Tissue-type plasminogen activator-mediated shedding of astrocytic low-density lipoprotein receptor-related protein increases the permeability of the neurovascular unit
Blood,
April 15, 2007;
109(8):
3270 - 3278.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. P. Lopez-Atalaya, B. D. Roussel, C. Ali, E. Maubert, K.-U. Petersen, V. Berezowski, R. Cecchelli, C. Orset, and D. Vivien
Recombinant Desmodus rotundus Salivary Plasminogen Activator Crosses the Blood-Brain Barrier Through a Low-Density Lipoprotein Receptor-Related Protein-Dependent Mechanism Without Exerting Neurotoxic Effects
Stroke,
March 1, 2007;
38(3):
1036 - 1043.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Akkawi, T. Nassar, M. Tarshis, D. B. Cines, and A. A.-R. Higazi
LRP and {alpha}vbeta3 mediate tPA activation of smooth muscle cells
Am J Physiol Heart Circ Physiol,
September 1, 2006;
291(3):
H1351 - H1359.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Ning, K. L. Furie, W. J. Koroshetz, H. Lee, M. Barron, M. Lederer, X. Wang, M. Zhu, A. G. Sorensen, E. H. Lo, et al.
Association between tPA therapy and raised early matrix metalloproteinase-9 in acute stroke
Neurology,
May 23, 2006;
66(10):
1550 - 1555.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Hu, J. Yang, S. Tanaka, S. L. Gonias, W. M. Mars, and Y. Liu
Tissue-type Plasminogen Activator Acts as a Cytokine That Triggers Intracellular Signal Transduction and Induces Matrix Metalloproteinase-9 Gene Expression
J. Biol. Chem.,
January 27, 2006;
281(4):
2120 - 2127.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. M. Armstead, D. B. Cines, and A. A.-R. Higazi
Plasminogen Activators Contribute to Impairment of Hypercapnic and Hypotensive Cerebrovasodilation After Cerebral Hypoxia/Ischemia in the Newborn Pig
Stroke,
October 1, 2005;
36(10):
2265 - 2269.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Tsuji, T. Aoki, E. Tejima, K. Arai, S.-R. Lee, D. N. Atochin, P. L. Huang, X. Wang, J. Montaner, and E. H. Lo
Tissue Plasminogen Activator Promotes Matrix Metalloproteinase-9 Upregulation After Focal Cerebral Ischemia
Stroke,
September 1, 2005;
36(9):
1954 - 1959.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Yu, A. H. Rux, P. Ma, K. Bdeir, and B. S. Sachais
Endothelial expression of E-selectin is induced by the platelet-specific chemokine platelet factor 4 through LRP in an NF-{kappa}B-dependent manner
Blood,
May 1, 2005;
105(9):
3545 - 3551.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Yepes and D. A. Lawrence
New Functions for an Old Enzyme: Nonhemostatic Roles for Tissue-Type Plasminogen Activator in the Central Nervous System
Experimental Biology and Medicine,
December 1, 2004;
229(11):
1097 - 1104.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
X. Wang, K. Tsuji, S.-R. Lee, M. Ning, K. L. Furie, A. M. Buchan, and E. H. Lo
Mechanisms of Hemorrhagic Transformation After Tissue Plasminogen Activator Reperfusion Therapy for Ischemic Stroke
Stroke,
November 1, 2004;
35(11_suppl_1):
2726 - 2730.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
