Regulation of tissue factor–induced signaling by endogenous and recombinant tissue factor pathway inhibitor 1

Abstract

Tissue factor (TF) triggers upstream coagulation signaling via the activation of protease-activated receptors (PARs) of relevance for inflammation and angiogenesis. TF pathway inhibitor 1 (TFPI-1) is the physiologic inhibitor of TF-initiated coagulation, but its role in regulating TF signaling is poorly understood. Here, we demonstrate that endogenous, endothelial cell-expressed TFPI-1 controls TFmediated signaling through PARs. In en IntroductionActivation of coagulation and cell signaling are interconnected by multiple pathways. Coagulation proteases signal via cleavage of protease-activated receptors (PARs), a family of G protein-coupled receptors with 4 known members (PAR1-PAR4). [1][2][3] The overlap in PAR signaling induced by different coagulation proteases, the partial redundancy between PARs, as well as possible intracellular cross-talk between PARs, make it challenging to distinguish the pathophysiologic significance of these signaling pathways. 4 Activation of coagulation by the tissue factor (TF) pathway is common in systemic and local inflammation. 5 In vivo, PAR signaling has generally been attributed to activation by thrombin. 1 However, our recent study has provided clear evidence for relevant thrombinindependent, TF-mediated PAR2 signaling in angiogenesis in vivo. 6 TF-dependent signaling is either by the TF-VIIa protease complex specifically through PAR2 7,8 or by the nascent product Xa in the ternary TF-VIIa-Xa complex that signals through PAR2 9,10 as well as PAR1, [8][9][10][11] the first recognized thrombin receptor.Tissue factor pathway inhibitor 1 (TFPI-1) is the central endogenous regulator of coagulation activation by TF. [12][13][14][15] Although purified TFPI-1 at high concentrations can inhibit TFVIIa, 16 efficient inhibition by TFPI-1 is dependent on Xa that is generated during TF-dependent initiation of coagulation. TFPI-1 contains 3 Kunitz-type protease inhibitor domains and a C-terminal polybasic region. The second domain binds and inhibits Xa, and TFPI-1 can thus act as a direct protease inhibitor of Xa. Kunitz domain 1 inhibits VIIa in complex with TF. 12,14,15 Endogenous TFPI-1 is directly or indirectly anchored by glycosylphosphatidylinositol (GPI) on cell surfaces. [17][18][19][20][21][22][23] Lipoprotein receptor-related protein (LRP) and heparan sulfate proteoglycan (HSPG) have been implicated in the binding and internalization of recombinant forms of TFPI-1, depending on their C-terminal polybasic portions. 24,25 Endothelial cells, which are normally deficient in LRP, may bind TFPI-1 via HSPG and the very-low-density lipoprotein receptor. 26,27 Moreover, intravenously administered [ 125 I]-TFPI-1 is rapidly cleared from the circulation, a process that seems to involve both LRP and HSPG. 28 However, there is no direct evidence to support a role for proteoglycans (PGs) in the regulation of TF-dependent PAR signaling by TFPI.The function of TFPI-1 as the physiologic inhibitor of TFinitiated coagulation has prompted interest in applying recombinant TFPI-1 (rTFPI-1) as a subs...

Rapid activation of monocyte tissue factor by antithymocyte globulin is dependent on complement and protein disulfide isomerase

“…For TFPI analysis, cells were incubated with 50 mg/mL polyclonal anti-TFPI 30 For personal use only. on May 11, 2018.…”

TFPIβ is the GPI-anchored TFPI isoform on human endothelial cells and placental microsomes

“…29 The TF/FVIIa complex triggers coagulation and, along with the transient TF/FVIIa/FXa complex, also signals proinflammatory responses through cell surface protease-activated receptors. 30 Only TFPI␣ containing a Kunitz-3 domain and C-terminus is a highly potent inhibitor of FXa. By comparison, full-length TFPI␣, truncated 2-Kunitz domain TFPI␣, and TFPI␤ each effectively inhibit the TF/FVIIa/FXa complex.…”

A preliminary estimation of tissue factor pathway inhibitor (TFPI) and protein C in patients with intracranial tumors

“…29 However, in intracranial tumor homogenates, a lowered TFPI concentration was noted. The literature analysis demonstrates that a lowered concentration of that inhibitor occurs in the active thrombotic process, in patients with a cerebro-vascular accident, as well as in patients undergoing serious operative procedures.…”