Human Protein C Receptor Is Present Primarily on Endothelium of Large Blood Vessels

Lászik, Zoltán; Mitro, A; Taylor, Fletcher B.; Ferrell, Gary; Esmon, Charles T.

doi:10.1161/01.cir.96.10.3633

Cited by 270 publications

(228 citation statements)

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“…Immunohistochemical studies revealed previously that EPCR expression is much greater on large vessel endothelium, particularly large arteries, and decreases until it is nearly undetectable in most capillary endothelial beds (9). The observation that protein C activation rates rise with increasing concentrations of EPCR provides the first evidence that there is an EPCR concentration dependence to protein C activation even when the EPCR concentration exceeds that of TM.…”

Section: Discussionmentioning

confidence: 78%

“…EPCR expression varies throughout the vasculature (9) and is sensitive to a variety of effector systems (5). In vivo, EPCR expression levels are highest on the endothelium of large vessels, decreasing progressively with decreasing vessel size until the EPCR becomes undetectable by immunohistochemical approaches in most capillary beds (9,10). With cultured endothelium, EPCR expression is down-regulated by cytokines like tumor necrosis factor ␣ (5, 11).…”

mentioning

confidence: 99%

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Reconstitution of the Human Endothelial Cell Protein C Receptor with Thrombomodulin in Phosphatidylcholine Vesicles Enhances Protein C Activation

Esmon

1999

Journal of Biological Chemistry

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Blocking protein C binding to the endothelial cell protein C receptor (EPCR) on the endothelium is known to reduce protein C activation rates. Now we isolate human EPCR and thrombomodulin (TM) and reconstitute them into phosphatidylcholine vesicles. The EPCR increases protein C activation rates in a concentration-dependent fashion that does not saturate at 14 EPCR molecules/TM. Without EPCR, the protein C concentration dependence fits a single class of sites (K m ‫؍‬ 2.17 ؎ 0.13 M). With EPCR, two classes of sites are apparent (K m ‫؍‬ 20 ؎ 15 nM and K m ‫؍‬ 3.2 ؎ 1.7 M). Increasing the EPCR concentration at a constant TM concentration increases the percentage of high affinity sites. Holding the TM: EPCR ratio constant while decreasing the density of these proteins results in a decrease in the EPCR enhancement of protein C activation, suggesting that there is little affinity of the EPCR for TM. Negatively charged phospholipids also enhance protein C activation. EPCR acceleration of protein C activation is blocked by anti-EPCR antibodies, but not by annexin V, whereas the reverse is true with negatively charged phospholipids. Human umbilical cord endothelium expresses approximately 7 times more EPCR than TM. Anti-EPCR antibody reduces protein C activation rates 7-fold over these cells, whereas annexin V is ineffective, indicating that EPCR rather than negatively charged phospholipid provide the surface for protein C activation. EPCR expression varies dramatically among vascular beds. The present results indicate that the EPCR concentration will determine the effectiveness of the protein C activation complex.

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Section: Discussionmentioning

confidence: 78%

mentioning

confidence: 99%

Reconstitution of the Human Endothelial Cell Protein C Receptor with Thrombomodulin in Phosphatidylcholine Vesicles Enhances Protein C Activation

Esmon

1999

Journal of Biological Chemistry

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“…Each of these mediators is differentially expressed across the vascular tree (reviewed in Rosenberg andAird 1999 andAird 2001). For example, the endothelial protein C receptor is primarily expressed in large vessels (Laszik et al 1997), tissue factor pathway inhibitor in microvessels (Osterud et al 1995), and tissue-type plasminogen activator in pulmonary and cerebral arteries (Levin et al 2000). In response to systemic inflammation, the expression of these various procoagulants and anticoagulants changes in ways that differ between vascular beds.…”

Section: Endothelial Cell Phenotypesmentioning

confidence: 99%

Endothelial Cell Heterogeneity

Aird

2011

Cold Spring Harbor Perspectives in Medicine

607

459

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“…EPCR, first cloned and characterized by the Esmon laboratory in the early 1990s, is primarily expressed by the vascular endothelium, preferentially on the endothelial cells of large blood vessels [5]. Recent studies have shown expression of EPCR in other cell types, including monocytes [6] and hematopoietic stem cells [7].…”

Section: Fviia Binding To Epcrmentioning

confidence: 99%

Factor VIIa binding to endothelial cell protein C receptor

Rao

Pendurthi

2008

Thrombosis Research

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Recent studies have shown that factor VIIa (FVIIa) binds specifically to endothelial protein C receptor (EPCR), a known cellular receptor for protein C and activated protein C, on the endothelium. The formation of FVIIa:EPCR complexes neither supports the activation of coagulation nor modulates tissue factor-initiated coagulation. However, FVIIa interaction with EPCR, particularly at pharmacological concentrations of FVIIa, may impair EPCR-dependent protein C activation and activated protein C-mediated cell signaling by competing directly with them for binding to EPCR. FVIIa binding to EPCR may also contribute to FVIIa clearance. This review summarizes recent data on FVIIa interaction with EPCR and discusses potential physiological significance and consequences of the interaction.

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Human Protein C Receptor Is Present Primarily on Endothelium of Large Blood Vessels

Abstract: These studies suggest that EPCR may be important in enhancing protein C activation on large vessels. The presence of high levels of EPCR on arterial vessels may help explain why partial protein C deficiency is a weak risk factor for arterial thrombosis.

Cited by 270 publications

References 32 publications

Reconstitution of the Human Endothelial Cell Protein C Receptor with Thrombomodulin in Phosphatidylcholine Vesicles Enhances Protein C Activation

Reconstitution of the Human Endothelial Cell Protein C Receptor with Thrombomodulin in Phosphatidylcholine Vesicles Enhances Protein C Activation

Endothelial Cell Heterogeneity

Factor VIIa binding to endothelial cell protein C receptor

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