LRP and αvβ3 mediate tPA activation of smooth muscle cells

2006 ◽  
Vol 291 (3) ◽  
pp. H1351-H1359 ◽  
Author(s):  
Sa'ed Akkawi ◽  
Taher Nassar ◽  
Mark Tarshis ◽  
Douglas B. Cines ◽  
Abd Al-Roof Higazi
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Plasminogen Activator ◽  
Vascular Smooth Muscle Cells ◽  
Density Lipoprotein ◽  
Plasminogen Activator Inhibitor ◽  
Muscle Cells ◽  
Tissue Type ◽  
Pai 1

Tissue-type plasminogen activator (tPA) regulates vascular contractility through the low-density lipoprotein-related receptor (LRP), and this effect is inhibited by plasminogen activator inhibitor type 1 (PAI-1). We now report that tPA-mediated vasocontraction also requires the integrin αvβ3. tPA-induced contraction of rat aortic rings is inhibited by the Arg-Gly-Asp (RGD) peptide and by monoclonal anti-αvβ3 antibody. tPA induces the formation of a complex between LRP and αvβ3 in vascular smooth muscle cells. The three proteins are internalized within 10 min, causing the cells to become refractory to the readdition of tPA. LRP and αvβ3 return to the cell surface by 90 min, restoring cell responsiveness to tPA. PAI-1 and the PAI-1-derived hexapeptide EEIIMD abolish the vasocontractile activity of tPA and inhibit the tPA-mediated interaction between LRP and αvβ3. tPA induces calcium mobilization from intracellular stores in vascular smooth muscle cells, and this effect is inhibited by PAI-1, RGD, and antibodies to both LRP and αvβ3. These data indicate that tPA-mediated vasocontraction involves the coordinated interaction of LRP with αvβ3. Delineating the mechanism underlying these interactions and the nature of the signals transduced may provide new tools to regulate vascular tone and other consequences of tPA-mediated signaling.

scholarly journals Integration of non-SMAD and SMAD signaling in TGF-β1-induced plasminogen activator inhibitor type-1 gene expression in vascular smooth muscle cells

2008 ◽  
Vol 100 (12) ◽  
pp. 976-983 ◽  
Author(s):  
Rohan Samarakoon ◽  
Paul J. Higgins
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Map Kinase ◽  
Plasminogen Activator ◽  
Vascular Smooth Muscle Cells ◽  
Plasminogen Activator Inhibitor ◽  
Activator Inhibitor ◽  
Tgf Β1 ◽  
Pai 1

SummaryOverexpression of plasminogen activator inhibitor-1 (SER-PINE1, PAI-1), the major physiological inhibitor of pericellular plasmin generation, is a significant causative factor in the progression of vascular disorders (e.g. arteriosclerosis, thrombosis, perivascular fibrosis) as well as a biomarker and a predictor of cardiovascular-disease associated mortality. PAI-1 is a temporal/ spatial regulator of pericellular proteolysis and ECM accumulation impacting, thereby, vascular remodeling, smooth muscle cell migration, proliferation and apoptosis. Within the specific context of TGF-β1-initiated vascular fibrosis and neointima formation, PAI-1 is a member of the most prominently expressed subset of TGF-β1-induced transcripts. Recent findings implicate EGFR/pp60c-src →MEK/ERK1/2 and Rho/ROCK→SMAD2/3 signaling in TGF-β1-stimulated PAI-1 expression in vascular smooth muscle cells. The EGFR is a direct upstream regulator of MEK/ERK1/2 while Rho/ROCK modulate both the duration of SMAD2/3 phosphorylation and nuclear accumulation. E-box motifs (CACGTG) in the PE1/PE2 promoter regions of the human PAI-1 gene, moreover, are platforms for a MAP kinase-directed USF subtype switch (USF-1→USF-2) in response to growth factor addition suggesting that the EGFR→MEK/ERK axis impacts PAI-1 expression, at least partly, through USF-dependent transcriptional controls. This paper reviews recent data suggesting the essential cooperativity among the EGFR→MAP kinase cascade, the Rho/ROCK pathway and SMADs in TGF-β1-initiated PAI-1 expression. The continued clarification of mechanistic controls on PAI-1 transcription may lead to new targeted therapies and clinically-relevant options for the treatment of vascular diseases in which PAI-1 dysregulation is a major underlying pathogenic feature.

scholarly journals Vascular Smooth Muscle Cells Potentiate Plasmin Generation by Both Urokinase and Tissue Plasminogen Activator-Dependent Mechanisms: Evidence for a Specific Tissue-Type Plasminogen Activator Receptor on These Cells

Blood ◽  
1997 ◽  
Vol 90 (6) ◽  
pp. 2312-2322 ◽  
Author(s):  
Vincent Ellis ◽  
Simon A. Whawell
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Plasminogen Activator ◽  
Vascular Smooth Muscle Cells ◽  
Muscle Cells ◽  
Tissue Type ◽  
Affinity Binding ◽  
Tissue Type Plasminogen Activator ◽  
Type Plasminogen Activator

Plasminogen activators play a role in the response of the vessel wall to injury, presumably by mediating the degradation of extracellular matrix (ECM) by vascular smooth muscle cells (VSMCs) that is necessary for their migration and proliferation. We have therefore investigated the ability of VSMCs to assemble specific cell surface plasminogen-activating systems. Urokinase-type plasminogen activator (uPA) bound to a single class of site on VSMCs (kd, 2 nmol/L), binding of pro-uPA resulted in a large potentiation of plasmin generation and both were competed by antibodies to the uPA receptor (uPAR). Tissue-type plasminogen activator (tPA) also bound to VSMCs as determined by functional assay, with the binding isotherms showing two classes of binding site with apparent kds of 25 and 300 nmol/L. tPA binding to the higher affinity site caused a greater than 90-fold enhancement of the activation of cell bound plasminogen, whereas the lower affinity binding, mediated primarily by the ECM, had little effect on tPA activity. The high-affinity binding of tPA to VSMCs resulted in an eightfold greater potential for plasmin generation than the binding of uPA, with this difference increasing to 15-fold after thrombin stimulation of the cells due to a 1.8-fold increase in tPA binding. These data show a novel specific tPA receptor on VSMCs that may be important for the regulation of plasminogen activation in various vascular pathologies.

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