Tissue factor is rapidly induced in arterial smooth muscle after balloon injury.

Marmur, Jonathan D.; Rossikhina, Maria; Guha, Anirban; Fyfe, Billie; Friedrich, Victor L.; Mendlowitz, Milton; Nemerson, Yale; Taubman, Mark B.

doi:10.1172/jci116452

Cited by 227 publications

(123 citation statements)

References 45 publications

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“…Because factor Xa generation occurs following intravascular injury for a long period of time (50,51) and factor Xa-mediated MMP-2 activation is robust, it can exert deleterious effects on tissues unless it is tightly regulated. Regulation of MMP-2 activity occurs at multiple levels, including gene expression, compartmentalization, zymogen activation, and enzyme inactivation by extracellular inhibitors, such as TIMPs (3).…”

Section: Discussionmentioning

confidence: 99%

Regulatory Mechanism of Matrix Metalloprotease-2 Enzymatic Activity by Factor Xa and Thrombin

Koo

Park

Jeon³

et al. 2009

Journal of Biological Chemistry

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Matrix metalloprotease (MMP)-2 plays a key role in many biological and pathological processes related to cell migration, invasion, and mitogenesis. MMP-2 is synthesized as a zymogen that is activated through either a conformational change or proteolysis of the propeptide. Several activating enzymes for pro-MMP-2 have been proposed, including metalloproteases and serine proteases. The mechanism of pro-MMP-2 activation by metalloproteases is well established, and the most studied activation mechanism involves cleavage of the propeptide by membrane type 1-MMP (MT1-MMP). In contrast, serine protease activation has not been thoroughly studied, although studies suggest that MT1-MMP may be involved in activation by thrombin and plasmin. Here, we demonstrate that factor Xa mediates MT1-MMP-independent processing of pro-MMP-2 in vascular smooth muscle cells and endothelial cells. Factor Xa and thrombin directly cleaved the propeptide on the carboxyl terminal sides of the Arg 98 and Arg 101 residues, whereas plasmin only cleaved the propeptide downstream of Arg 101 . Moreover, processed MMP-2 showed enzymatic activity that was enhanced by intermolecular autoproteolytic processing at the Asn 109 -Tyr peptide bond. In addition to its role in activation, factor Xa rapidly degraded MMP-2, thereby restricting excessive MMP-2 activity. Thrombin also degraded MMP-2, but the degradation was reduced greatly under cell-associated conditions, resulting in an increase in processed MMP-2. Overall, factor Xa and thrombin regulate MMP-2 enzymatic activity through its activation and degradation. Thus, the net enzymatic activity results from a balance between MMP-2 activation and degradation. Matrix metalloprotease (MMP)3 -2 is a member of the zincdependent endopeptidase family, which comprises 24 enzymes (1). MMP-2 plays a key role in many biological and pathological processes, including organ growth, endometrial cycling, wound healing, bone remodeling, tumor invasion, and metastasis (2). This enzyme functions through proteolysis of non-structural extracellular molecules and components of the basement membrane, including type IV collagen, fibronectin, elastin, laminin, aggrecan, and fibrillin (3).Like most MMPs, MMP-2 is synthesized as a zymogen that is activated by conformational change (4) or proteolysis within the propeptide, which may involve membrane type MMPs (MT-MMPs) (5-9). The most studied activation mechanism for pro-MMP-2 is cleavage of the propeptide by MT1-MMP, which requires cooperative activity between MT1-MMP and tissue inhibitor of metalloprotease (TIMP)-2 (5, 10 -12). Serine proteases, such as thrombin, factor Xa, activated protein C, and plasmin as well as the cysteine protease legumain are all known activators of pro-MMP-2 (13-17). (25,26). Both proteases can also elicit endothelial cell and SMC migration through pro-MMP-2 activation and subsequent extracellular matrix degradation (13,27,28). However, despite studies suggesting that MT1-MMP is involved in thrombin-mediated activation of pro-MMP-2, a detailed mechanism...

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Section: Discussionmentioning

confidence: 99%

Regulatory Mechanism of Matrix Metalloprotease-2 Enzymatic Activity by Factor Xa and Thrombin

Koo

Park

Jeon³

et al. 2009

Journal of Biological Chemistry

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“…20 A no. 2 Fogarty balloon embolectomy catheter was introduced via the femoral artery and advanced to the level of the aortic arch.…”

Section: Balloon Injury In Ratsmentioning

confidence: 99%

EGFL7 Is a Chemoattractant for Endothelial Cells and Is Up-Regulated in Angiogenesis and Arterial Injury

Campagnolo¹,

Leahy²,

Chitnis³

et al. 2005

The American Journal of Pathology

122

150

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The endothelium of the adult vasculature is normally quiescent, with the exception of the vasculature of the female reproductive system. However, in response to appropriate stimuli (ie, wound healing, atherosclerosis, tumor growth and metastasis, arthritis) the vasculature becomes activated and grows new capillaries through angiogenesis. We have recently identified a novel endothelial-restricted gene, Egfl7, that encodes a 41-kd secreted protein (Fitch MJ, Campagnolo L, Kuhnert F, Stuhlmann H: Egfl7, a novel epidermal growth factor-domain gene expressed in endothelial cells. Dev Dyn 2004, 230:316 -324). Egfl7 is expressed at high levels early during mouse embryonic development and is strictly associated with the vascular bed. In this study, we investigated Egfl7 expression in the quiescent adult vasculature, in the pregnant uterus, and in two different models of arterial injury, namely ballooning and ferric chloride injury. By RNA in situ hybridization, Egfl7 expression in the vasculature was found to be restricted to the endothelium of the capillaries and mature vessels. In the pregnant uterus, increased vascularization was accompanied by up-regulation of Egfl7. On arterial injury, Egfl7 expression was up-regulated in the regenerating endothelium, but not in the neointima. Importantly, the EGFL7 protein acted as a chemoattractant for embryonic endothelial cells and fibroblasts in a cell migration assay. Together, these results suggest that Egfl7 functions in the formation and maintenance of endothelial integrity and that its up- In the adult mammalian organism, the vasculature is normally quiescent. Arterial endothelial cells have an extremely low turnover rate (ϳ1 in every 10 5 cells undergoes cell division 1 ). However, adult endothelial cells are not postmitotic and, in response to appropriate stimuli, they can proliferate and form new blood vessels by a process termed angiogenesis. 2-4 Angiogenesis describes the formation of new capillaries and larger vessels by sprouting or splitting from pre-existing vessels. Typically, the sprouting of vessels involves activation of quiescent endothelial cells, proteolytic degradation of the extracellular matrix, chemotactic migration, invasion into the surrounding stroma, proliferation and differentiation of endothelial cells, and formation of a new lumen and maturation of the endothelium. 2,[5][6][7][8] This angiogenic sprouting process occurs under physiological conditions during the female reproductive cycle (ovulation, implantation, pregnancy) and wound healing, as well as under pathological conditions in solid tumors and metastases, rheumatoid arthritis, retinopathies, hemangiomas, and psoriasis. 2,7,9,10 Several of the key players in both embryonic and adult angiogenesis are vascular-specific growth factor ligands

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“…The expression of TF mRNA in normal vascular endothelial cells (ECs) in vivo is undetectable. Its expression, however, is increased in a variety of pathological conditions, including in atherosclerotic plaques (5,6) and in arterial smooth muscle cells after balloon injury (7). Chemical stimuli such as phorbol ester 12-O -tetradecanoyl-13-phorbol-acetate (TPA), tumor necrosis factor-␣ (TNF-␣ ), bacterial endotoxin LPS, and IL-1 ␤ induce the expression of TF mRNA in cultured ECs (8)(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

Shear stress induction of the tissue factor gene.

et al. 1997

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Using flow channel, we report that the application of a laminar shear stress induced a transient increase of tissue factor (TF) procoagulant activity in human umbilical vein endothelial cells (HUVEC), which was accompanied by a rapid and transient induction of the TF mRNA in the HUVEC. Functional analysis of the 2.2 kb TF 5 Ј promoter indicated that a GC-rich region containing three copies each of the EGR-1 and Sp1 sites was required for induction. Mutation of the Sp1 sites, but not the EGR-1 sites, attenuated the response of TF promoter to shear stress. Thus, Sp1 is a newly defined shear stress responsive element. Electrophoretic mobility shift assays showed there was no increase in binding of nuclear extracts from sheared cells to an Sp1 consensus site. In contrast, immunoblotting of these nuclear extracts with antibody against transcription factor Sp1 demonstrated that shear stress increased the phosphorylation of Sp1. We also showed that shear stress, like the phosphatase inhibitor okadaic acid, increased the transcriptional activity of Sp1. These findings suggest that the shear stress induction of TF gene expression is mediated through an increased Sp1 transcriptional activity with a concomitant hyperphosphorylation of Sp1. ( J. Clin. Invest. 1997. 99:737-744.)

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Tissue factor is rapidly induced in arterial smooth muscle after balloon injury.

Cited by 227 publications

References 45 publications

Regulatory Mechanism of Matrix Metalloprotease-2 Enzymatic Activity by Factor Xa and Thrombin

Regulatory Mechanism of Matrix Metalloprotease-2 Enzymatic Activity by Factor Xa and Thrombin

EGFL7 Is a Chemoattractant for Endothelial Cells and Is Up-Regulated in Angiogenesis and Arterial Injury

Shear stress induction of the tissue factor gene.

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