Von Willebrand factor present in fibrillar collagen enhances platelet adhesion to collagen and collagen-induced platelet aggregation

Bernardo, Aubrey; Bergeron, Angela L.; Sun, Carol; Guchhait, Prasenjit; Crúz, Miguel A.; López, José A.; Dong, Jing

doi:10.1111/j.1538-7836.2004.00661.x

Cited by 37 publications

(37 citation statements)

References 45 publications

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“…Certainly, the partial blockade of the GPVI binding site on collagen could account for some of the effects of CTRP-1 under these conditions. In addition, a recent report by Bernardo et al 36 demonstrates that fibrillar collagen as used in the current studies is contaminated with small amounts of VWF. Although the role of VWF clearly is to mediate the initial interaction of platelets with injured vasculature and exposed collagen under high-shear conditions seen in arterial vasculature, a contribution to platelet aggregation under static in vitro conditions cannot be excluded.…”

Section: In Vivo Antithrombotic Effects Of Ctrp-1 In a Folts Vascularmentioning

confidence: 66%

C1qTNF–related protein-1 (CTRP-1): a vascular wall protein that inhibits collagen-induced platelet aggregation by blocking VWF binding to collagen

Lasser

Guchhait

Ellsworth

et al. 2006

Blood

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CTRP-1 is a novel member of the C1q-TNF-related protein family containing family characteristic collagen and TNFlike domains and shows marked expression in vascular wall tissue. We observed that recombinant human CTRP-1 specifically bound to fibrillar collagen and blocked collagen-induced platelet aggregation. CTRP-1 completely or partially prevented VWF and GPVI-Fc4 binding to collagen, respectively. However, GPVIFc4 failed to compete for the binding of CTRP-1 to collagen. CTRP-1 had no effects on ␣ 2 ␤ 1 integrin I-domain binding to collagen. Using whole human blood under flow at low and high shear rates, CTRP-1 prevented platelets from accumulating on a collagen-coated surface but had no effects on "platelet-rolling" on a surface coated with VWF. These data suggest that CTRP-1 prevents collagen-induced platelet aggregation by specific blockade of VWF binding to collagen. By using the Folts vascular injury model in nonhuman primates (Macaca fascicularis), we were able to demonstrate that CTRP-1 can prevent platelet thrombosis in vivo. This effect was achieved in the absence of changes in activated-clotting time (ACT) and template cut bleeding times, suggesting that CTRP-1 has promising antiplatelet thrombotic activity and most likely acts by pacifying the thrombogenic site of vascular injury. IntroductionC1qTNF-related protein-1 (CTRP-1) belongs to a family of proteins characterized by a common TNF alpha-like globular domain. 1-3 A second, less conserved structural element in this family is the N-terminal collagen-like region with typical glycine-X-Y repeats. The basic structure of proteins in the CTRP family appears to be a trimer that, in turn, can form higher order structures. 4 While structurally related, members of this protein family are functionally diverse and include the plasma protein C1q, which is involved in immune functions and possibly platelet hemostasis, 5 and adiponectin 6-8 and the hibernation proteins 20, 25, and 27, which are thought to be regulators of metabolism 9 ; other CTRP family members appear to have more structural or extracellular matrix-related functions (eg, collagen types VIII and X,. 10 Since C1q may play a role in collagen-induced platelet activation, 11 we investigated whether CTRP-1 might exhibit similar properties. Initial studies indicated that CTRP-1 had affinity for collagen and blocked collagen-induced platelet activation. This raises the potential significance of CTRP-1 for human disease because of the central role collagen-induced platelet activation and thrombus formation play in acute cardiovascular and cerebrovascular events. Spontaneous rupture of atherosclerotic plaque or medical interventions can cause an injury to the arterial endothelial lining, thus exposing the subendothelial extracellular matrix to circulating blood. Collagens are a major component of the extracellular matrix and can directly and indirectly activate platelets. [12][13][14][15][16] Three platelet receptors are thought to mediate these interactions. Integrin ␣ 2 ␤ 1 is thought to have a ma...

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Section: In Vivo Antithrombotic Effects Of Ctrp-1 In a Folts Vascularmentioning

confidence: 66%

C1qTNF–related protein-1 (CTRP-1): a vascular wall protein that inhibits collagen-induced platelet aggregation by blocking VWF binding to collagen

Lasser

Guchhait

Ellsworth

et al. 2006

Blood

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“…However, washed platelets in a buffer lack VWF. The adhesion of washed platelets to collagen in our experiments can be explained by the fact that fibrillary collagen contains VWF [30] . In this setup, we found that EP3 receptor activation caused an increase in adherent platelets.…”

Section: Discussionmentioning

confidence: 96%

The EP3 Agonist Sulprostone Enhances Platelet Adhesion But Not Thrombus Formation Under Flow Conditions

Pasterk

Philipose²,

Eller³

et al. 2015

Pharmacology

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Platelets express the EP2, EP3 and EP4 receptors. Prostaglandin (PG) E₂ has a biphasic effect on platelets. Low concentrations of PGE₂ enhance platelet aggregation through the activation of the EP3 receptors, while at high concentrations it attenuates aggregation via the EP4 receptor. Consequently, EP3 receptor inhibition was shown to inhibit artherothrombosis, but had no influence on bleeding time in vivo. In this study, we investigated the role of the EP3 receptor in adhesion and thrombus formation under flow conditions in vitro. The EP3 agonist sulprostone caused an increase in the adhesion of washed platelets to fibrinogen as well as to collagen under low shear stress, an effect that was blocked by the EP3 antagonist L-798106. In contrast, when whole blood was perfused over collagen-coated surfaces, sulprostone did not enhance binding and thrombus formation of platelets on collagen; at high concentrations it even attenuated this response. We conclude that in more physiological models of thrombus formation, the role for EP3 receptors is limited, indirectly suggesting that the primary action of PGE₂ in haemostasis might be an inhibitory one.

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“…This apparent discrepancy with published results showing that both GPIb and ␣2␤1 contribute to primary adhesion under flow in these shear stress conditions (43) may be due to the low density of collagen (0.08 g/cm 2 ), precluding plasma vWF binding, and/or the low levels of fibrillar collagen at this density of collagen (0.08 g/cm 2 ). In either case, platelet ␣2␤1 function is essential for irreversible platelet attachment, even at high shear stress (45). Savage et al (44) reported that ␣2␤1 inhibition completely prevented platelet adhesion to acid-soluble collagen but had no effect on binding to native insoluble fibrillar collagen.…”

Section: Involvement Of P38 and Erk2 In Platelet Adhesion To Collagenmentioning

confidence: 99%

“…We cannot rule out the possible gradual production of fibrillar collagen from acid-soluble collagen, leading to the activation of GPVI, enhancing adhesion by inside-out signaling to ␣2␤1. Such differences in collagen structure have been reported to be directly related to differences in vWF content (45). In pathological conditions such as atherogenesis, in vivo studies have shown that collagen fibers may be degraded because of an increase in the matrix metalloproteinase activity of infiltrating macrophages and activated smooth muscle cells (46).…”

Section: Involvement Of P38 and Erk2 In Platelet Adhesion To Collagenmentioning

confidence: 99%

Differential Involvement of ERK2 and p38 in Platelet Adhesion to Collagen

Mazharian

Roger

Maurice

et al. 2005

Journal of Biological Chemistry

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We investigated the role of two MAP kinases, ERK2 and p38, in platelet adhesion and spreading over collagen matrix in static and blood flow conditions. P38 was involved in collagen-induced platelet adhesion and spreading in static adhesion conditions, whereas ERK2 was not. In blood flow conditions, with shear rates of 300 or 1500 s ؊1 , ERK2 and p38 displayed differential involvement in platelet adhesion, depending on the presence or absence of the von Willebrand factor (vWF). Low collagen coverage densities (0.04 g/cm 2 ) did not support vWF binding. During perfusions over this surface, platelet adhesion was not affected by the inhibition of ERK2 phosphorylation by PD 98059. However, abolishing p38 activation by SB 203580 treatment reduced platelet adhesion by 67 ؎ 9% at 300 s ؊1 and 56 ؎ 2% at 1500 s ؊1 . In these conditions, the p38 activity required for platelet adhesion depends on the ␣2␤1 collagen receptor. At higher collagen coverage densities (0.8 g/cm 2 ) supporting vWF binding, the inhibition of ERK2 activity by PD 98059 decreased adhesion by 47 ؎ 6% at 300 s ؊1 and 72 ؎ 3% at 1500 s ؊1 , whereas p38 inhibition had only a small effect. The ERK2 activity required for platelet adhesion was dependent on the interaction of vWF with GPIb. In conclusion, ERK2 and p38 have complementary effects in the control of platelet adhesion to collagen in a shear stress-dependent manner.The adhesion and aggregation of platelets in response to vascular injury plays a key role in hemostasis and thrombosis. Fibrillar collagen is the most abundant thrombogenic molecule among the macromolecular constituents of the subendothelial layer. Following exposure to collagen, platelets rapidly adhere, spread, become active, and then aggregate (1, 2). This interaction of collagen with platelets is both direct and indirect. Under the high shear stress conditions found in small arteries, the von Willebrand factor (vWF), 1 which binds to newly exposed collagen fibers, is required to capture flowing platelets (3) via the GPIb-IX-V complex on the platelet surface. This interaction (vWF-GPIb) cannot support the assembly of a stable platelet thrombus. Subsequent firm platelet adhesion and activation are mediated by two major surface receptors for collagen, the integrin ␣2␤1 and glycoprotein VI (4 -6). The relative contributions of these two receptors to collagen-mediated adhesion are unclear, and various models have been proposed (7). According to the two-site, two-step model, the major candidate for involvement in platelet deposition and stabilization on collagen is ␣2␤1, with GPVI mediating activation and initiating the signaling pathway involved in thrombus formation (8). Platelet activation leads to an increase in the affinity of ␣2␤1, which in turn leads to an increase in adhesion stability. Another model has been proposed in which the absence of functional GPVI impairs adhesion under static and shear conditions (9, 10). In this model, GPVI initiates signaling pathways, leading to the activation of the ␣2␤1 integrin and of other integri...

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Von Willebrand factor present in fibrillar collagen enhances platelet adhesion to collagen and collagen-induced platelet aggregation

Cited by 37 publications

References 45 publications

C1qTNF–related protein-1 (CTRP-1): a vascular wall protein that inhibits collagen-induced platelet aggregation by blocking VWF binding to collagen

C1qTNF–related protein-1 (CTRP-1): a vascular wall protein that inhibits collagen-induced platelet aggregation by blocking VWF binding to collagen

The EP3 Agonist Sulprostone Enhances Platelet Adhesion But Not Thrombus Formation Under Flow Conditions

Differential Involvement of ERK2 and p38 in Platelet Adhesion to Collagen

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