Expression of Tissue Factor Pathway Inhibitor in Vascular Smooth Muscle Cells and Its Regulation by Growth Factors

Caplice, Noel M.; Mueske, Cheryl S.; Kleppe, Laurel S.; Peterson, Timothy E.; Broze, George J.; Simari, Robert D.

doi:10.1161/01.res.83.12.1264

Cited by 59 publications

(46 citation statements)

References 27 publications

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“…39,40 Given that Tie2 directed deletion of TFPI-K1 results in a 71% reduction in circulating TFPI activity, there must be a nonendothelial and nonhematopoietic cell-derived source for TFPI. Potential sources include vascular smooth muscle cells 7 or cardiomyocytes. 46 Examination of the LysM, Tie2, and bone marrow cell contributions to circulating TFPI activity would suggest that approximately 50% of circulating TFPI activity comes from endothelium.…”

Section: Discussionmentioning

confidence: 99%

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Endothelial-derived tissue factor pathway inhibitor regulates arterial thrombosis but is not required for development or hemostasis

White

Johnson

Zarzhevsky

et al. 2010

Blood

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The antithrombotic surface of endothelium is regulated in a coordinated manner. Tissue factor pathway inhibitor (TFPI) localized at the endothelial cell surface regulates the production of FXa by inhibiting the TF/VIIa complex. Systemic homozygotic deletion of the first Kunitz (K1) domain of TFPI results in intrauterine lethality in mice. Here we define the cellular sources of TFPI and their role in development, hemostasis, and thrombosis using TFPI conditional knockout mice. We used a Cre-lox strategy and generated mice with a floxed exon 4 (TFPI Flox ) which encodes for the TFPI-K1 domain. Mice bred into Tie2-Cre and LysM-Cre lines to delete TFPI-K1 in endothelial (TFPI Tie2 ) and myelomonocytic (TFPI LysM ) cells resulted in viable and fertile offspring. Plasma TFPI activity was reduced in the TFPI Tie2 (71% ؎ 0.9%, P < .001) and TFPI LysM (19% ؎ 0.6%, P < .001) compared with TFPI Flox littermate controls. Tail and cuticle bleeding were unaffected. However, TFPI Tie2 mice but not TFPI LysM mice had increased ferric chlorideinduced arterial thrombosis. Taken together, the data reveal distinct roles for endothelial-and myelomonocytic-derived TFPI. (Blood. 2010;116(10):1787-1794) IntroductionThe endothelium provides an antithrombotic interface with circulating blood which is generated in part by the coordinated expression of endothelial-derived anticoagulants. The regulated expression of these endothelial-derived proteins may account in part for differences in thrombotic phenotype among vessels. 1 Tissue factor pathway inhibitor (TFPI) is a Kunitz-type serine protease inhibitor expressed in endothelial cells and regulates the initiation of coagulation by inhibiting tissue factor (TF)/factor VIIa activation of factor X.TFPI, originally known as lipoprotein associated coagulation inhibitor, was isolated from a hepatoma cell line. 2 TFPI circulates at low (nmol/L) levels in humans largely associated with lipoproteins. 3 Infusion of heparin increases circulating levels of TFPI in humans, and this increase has been attributed to displacement of TFPI from glycosoaminoglycans on the surface of endothelial cells. 4,5 As such, the endothelium has been thought to be the dominant source of circulating TFPI. However, TFPI is also expressed in platelets, vascular smooth muscle, cardiac myocytes, and monocyte/macrophages. 4,[6][7][8][9][10] The physiologic importance of TFPI is confirmed in that no known human deficiencies of TFPI have been reported. Homozygotic deletion of exon 4 in mice (which encodes the Kunitz 1 domain) resulted in embryonic lethality. 11 Heterozygotic deletion results in an increased response to acute and chronic vascular injury. [12][13][14] Conversely, vasculardirected overexpression of TFPI attenuates this response. 15 To better define the cellular sources of TFPI and their role in development, hemostasis, and thrombosis, we generated mice with endothelial and monocytic-restricted deletion of exon 4, which encodes for the TFPI-K1 domain. We also used bone marrow transplantation as a means to generate ...

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Section: Discussionmentioning

confidence: 99%

“…However, TFPI is also expressed in platelets, vascular smooth muscle, cardiac myocytes, and monocyte/macrophages. 4,[6][7][8][9][10] The physiologic importance of TFPI is confirmed in that no known human deficiencies of TFPI have been reported. Homozygotic deletion of exon 4 in mice (which encodes the Kunitz 1 domain) resulted in embryonic lethality.…”

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Endothelial-derived tissue factor pathway inhibitor regulates arterial thrombosis but is not required for development or hemostasis

White

Johnson

Zarzhevsky

et al. 2010

Blood

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“…Generation of 293 Cell Lines Stably Expressing EGFP-TFPI and Cav1-HPC4ep-HEK293 express low levels of both Cav-1 (25,26) and TFPI (27). We transfected 293 cells with pEGFP-C 2 /TFPI(C), pSVzeoCav1-HPC4ep, or co-transfected with both vectors using PolyFect (Qiagen; efficiency ϳ50 -70%).…”

Section: Methodsmentioning

confidence: 99%

Caveolin-1 Enhances Tissue Factor Pathway Inhibitor Exposure and Function on the Cell Surface

Lupu

2005

Journal of Biological Chemistry

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Tissue factor pathway inhibitor (TFPI) blocks tissue factor-factor VIIa (TF-FVIIa) activation of factors X and IX through the formation of the TF-FVIIa-FXa-TFPI complex. Most TFPI in vivo associates with caveolae in endothelial cells (EC). The mechanism of this association and the anticoagulant role of caveolar TFPI are not yet known. Here we show that expression of caveolin-1 (Cav-1) in 293 cells keeps TFPI exposed on the plasmalemma surface, decreases the membrane lateral mobility of TFPI, and increases the TFPI-dependent inhibition of TF-FVIIa. Caveolae-associated TFPI supports the co-localization of the quaternary complex with caveolae. To investigate the significance of these observations for EC we used RNA interference to deplete the cells of Cav-1. Functional assays and fluorescence microscopy revealed that the inhibitory properties of TFPI were diminished in EC lacking Cav-1, apparently through deficient assembly of the quaternary complex. These findings demonstrate that caveolae regulate the inhibition by cell-bound TFPI of the active protease production by the extrinsic pathway of coagulation.Tissue factor (TF) 1 is a transmembrane protein that triggers blood coagulation in vivo. Assembly of TF with factor VIIa (FVIIa) on cell surfaces initiates limited proteolysis of factors IX and X (FX), leading to thrombin generation. TF elicits thrombogenic responses in septicemia, cancer, and atherosclerosis (1-4), promotes metastasis, angiogenesis, and intima hyperplasia after arterial injury (5, 6), and acts as signaling receptor upon binding of FVIIa (7).Tissue factor pathway inhibitor (TFPI) is the endogenous regulator of TF-FVIIa activity. TFPI is a Kunitz-type protease inhibitor, which binds FVIIa via Kunitz-1 and FXa via Kunitz-2. Formation of the TF-FVIIa-FXa-TFPI complex provides sustained repression of the TF pathway (8). TFPI was first described as a soluble plasma protein that binds through its C terminus to yet uncharacterized anionic sites on the cell surface. Nevertheless, the majority of TFPI circulating in plasma is C-terminal truncated and bound to plasma lipoproteins, and as such, has significantly less inhibitory activity than the full-length TFPI (9).TFPI in vivo is mainly produced by endothelial cells (EC), has an intact C terminus, and associates with the plasma membrane through mechanisms that are not fully identified (3, 10 -13). Heparin releases a portion of the full-length, functionally active cell-associated TFPI, either from cell surface-binding sites or from intracellular stores (14, 15). However, the bulk of heparin-resistant cellular TFPI is released by phosphatidylinositol-phospholipase C in vitro, which indicates that most cellular TFPI associates with the cell surface via a glycosylphosphatidylinositol link (10 -12, 16, 17). Furthermore, endogenous TFPI in resting endothelium (10), monocytes (18), and the ECV304 cell line (11, 16) partitions in low-density fractions insoluble in cold detergent (lipid rafts). In monocytes and ECV304 endogenous TFPI inhibits efficiently FVIIa-TF...

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“…It has been estimated that about 85% of intravascular TFPI is located on the surface of endothelial cells (9), with the remainder within platelets (10,11) and in circulating plasma (12). Small amounts of TFPI have been identified on monocytes (13) and vascular smooth muscle cells (14) as well as other cell types (15). Although most intravascular TFPI is thought to be exposed to circulating blood, TFPI is also present within endothelial cells, with acute release following exposure to thrombin (16,17), and within platelets, with release following dual agonist activation with thrombin plus collagen (10,11).…”

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Absence of hematopoietic tissue factor pathway inhibitor mitigates bleeding in mice with hemophilia

Maroney

Cooley

Ferrel

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Tissue factor pathway inhibitor (TFPI) blocks thrombin generation via the extrinsic blood coagulation pathway. Because the severe bleeding in patients with hemophilia occurs from deficiency of intrinsic blood coagulation pathway factor VIII or IX, pharmacological agents that inactivate TFPI and, therefore, restore thrombin generation via the extrinsic pathway, are being developed for treatment of hemophilia. Murine models of combined TFPI and factor VIII deficiency were used to examine the impact of TFPI deficiency on bleeding and clotting in hemophilia. In breeding studies, Factor VIII null (F8 −/− ) did not rescue the embryonic death of TFPI null (Tfpi −/− ) mice. Tfpi +/− did not alter the bleeding phenotype of F8 −/− mice. However, total inhibition of intravascular TFPI through injection of anti-TFPI antibody mitigated tail vein bleeding. Interestingly, tail blood loss progressively decreased at doses greater than needed to totally inhibit plasma TFPI, suggesting that inhibition of a sequestered pool of TFPI released at the injury site mitigates bleeding. Because TFPI is sequestered within platelets and released following their activation, the function of platelet TFPI was examined in F8 −/− mice lacking hematopoietic cell TFPI that was generated by fetal liver transplantation. Blood loss after tail transection significantly decreased in Tfpi +/− ;F8 −/− mice with hematopoietic Tfpi −/− cells compared with Tfpi +/− ;F8 −/− mice with Tfpi +/+ hematopoietic cells. Additionally, following femoral vein injury, Tfpi +/− ;F8 −/− mice with Tfpi −/− hematopoietic cells had increased fibrin deposition compared with identical-genotype mice with Tfpi +/+ hematopoietic cells. These findings implicate platelet TFPI as a primary physiological regulator of bleeding in hemophilia.hemostasis | Kunitz | coagulopathy

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Expression of Tissue Factor Pathway Inhibitor in Vascular Smooth Muscle Cells and Its Regulation by Growth Factors

Cited by 59 publications

References 27 publications

Endothelial-derived tissue factor pathway inhibitor regulates arterial thrombosis but is not required for development or hemostasis

Endothelial-derived tissue factor pathway inhibitor regulates arterial thrombosis but is not required for development or hemostasis

Caveolin-1 Enhances Tissue Factor Pathway Inhibitor Exposure and Function on the Cell Surface

Absence of hematopoietic tissue factor pathway inhibitor mitigates bleeding in mice with hemophilia

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