A Role for Thrombin Receptor Signaling in Endothelial Cells During Embryonic Development

Griffin, Courtney T.; Srinivasan, Yoga; Zheng, Yaowu; Huang, Wei; Coughlin, Shaun R.

doi:10.1126/science.1061259

Cited by 258 publications

(233 citation statements)

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“…The lethal embryonic phenotypes of embryos lacking some coagulation factors (e.g. tissue factor, prothrombin, factor X) must therefore be caused by mechanisms that are independent of the fibrin-platelet interaction and instead most likely related to the developmental function of PAR proteins in vascular and non-vascular tissues (Bugge et al, 1996;Camerer et al, 2010;Carmeliet et al, 1996;Cui et al, 1996;Griffin et al, 2001;Sun et al, 1998;Toomey et al, 1996;Xue et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

p45NF-E2 represses Gcm1 in trophoblast cells to regulate syncytium formation, placental vascularization and embryonic growth

et al. 2011

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SUMMARYAbsence of the leucine zipper transcription factor p45NF-E2 results in thrombocytopenia, impaired placental vascularization and intrauterine growth restriction (IUGR) in mice. The mechanism underlying the p45NF-E2-dependent placental defect and IUGR remains unknown. Here, we show that the placental defect and IUGR of p45NF-E2 (Nfe2) null mouse embryos is unrelated to thrombocytopenia, establishing that embryonic platelets and platelet-released mediators are dispensable for placentation. Rather, p45NF-E2, which was hitherto thought to be specific to hematopoietic cells, is expressed in trophoblast cells, where it is required for normal syncytiotrophoblast formation, placental vascularization and embryonic growth. Expression of p45NF-E2 in labyrinthine trophoblast cells colocalizes with that of Gcm1, a transcription factor crucial for syncytiotrophoblast formation. In the absence of p45NF-E2, the width of syncytiotrophoblast layer 2 and the expression of Gcm1 and Gcm1-dependent genes (Synb and Cebpa) are increased. In vitro, p45NF-E2 deficiency results in spontaneous syncytiotrophoblast formation, which can be reversed by Gcm1 knockdown. Increased Gcm1 expression in the absence of p45NF-E2 is dependent on enhanced protein acetylation, including post-translational modification of Gcm1. Increasing and inhibiting acetylation in the placenta of wild-type control embryos phenocopies and corrects, respectively, the changes observed in p45NF-E2-deficient embryos. These studies identify a novel function of p45NF-E2 during placental development: in trophoblast cells, p45NF-E2 represses Gcm1 and syncytiotrophoblast formation via acetylation.

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Section: Discussionmentioning

confidence: 99%

p45NF-E2 represses Gcm1 in trophoblast cells to regulate syncytium formation, placental vascularization and embryonic growth

et al. 2011

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“…Embryonic death of PAR-1-null mice can be prevented by targeted expression of PAR-1 in endothelial cells. 13 Although PAR-1 is expressed by platelets and mediates platelet aggregation in humans, PAR-1 is not expressed by mouse platelets, and therefore is not required for normal blood coagulation in this species. 14 A number of models of bone repair have been established for use in mice, including an unstabilized fracture model, stabilized fracture models involving internal or external fixation, and models involving bone defects without fracture.…”

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confidence: 99%

The Role of Protease-Activated Receptor-1 in Bone Healing

Song

Pagel

Campbell

et al. 2005

The American Journal of Pathology

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Protease-activated receptor (PAR)-1, a G-protein-coupled receptor activated by thrombin, mediates thrombin-induced proliferation of osteoblasts. The current study was undertaken to define the role of PAR-1 in bone repair. Holes were drilled transversely through the diaphysis of both tibiae of PAR-1-null and wildtype mice. Three days later, fewer cells had invaded the drill site from adjacent bone marrow in PAR-1-null mice than in wild-type mice, and a lower percentage of cells were labeled with [ 3 H]thymidine in PAR-1-null drill sites. More osteoclasts were also observed in the drill site of PAR-1-null mice than in wild-type mice 7 days after drilling. New mineralized bone area was less in the drill site and on the adjacent periosteal surface in PAR-1-null mice than in wildtype mice at day 9. From day 14, no obvious differences could be seen between PAR-1-null and wild-type tibiae. In vitro thrombin caused a dose-dependent increase in proliferation of bone marrow stromal cells isolated from wild-type mice but not PAR-1-null mice. Thrombin stimulated survival of bone marrow stromal cells from both wild-type and PAR-1-null mice, but it did not affect bone marrow stromal cell migration in either wild-type or PAR-1-null cells Thrombin is a serine protease, which plays a central role in blood coagulation through its cleavage of fibrinogen, but also exerts specific receptor-mediated effects on cell function. Three thrombin receptors have been identified, protease-activated receptors (PARs)-1, -3, and -4, which are members of the seven transmembrane domain Gprotein-coupled receptor family. 1,2 Protease-activated receptor-1 is expressed by osteoblasts (bone-forming cells), and mediates thrombin-induced proliferation of these cells. [3][4][5] Thrombin also stimulates osteoclastic bone resorption in vitro. 6,7 Thrombin is generated during tissue injury, and PAR-1 activation appears to be involved in pathological processes including inflammation and wound healing. 8 -10 For example, when thrombin or a PAR-1-activating peptide is applied to incisional skin wounds in rats, wound healing is accelerated. 11 Because both osteoblast proliferation and bone resorption are important components of the process of bone repair, we hypothesized that thrombin, through PAR-1, may participate in this process. The current study was undertaken to investigate this hypothesis, using mice with a targeted disruption of the PAR-1 gene. 12 Fifty percent of these mice die at about day 9.5 of gestation, and the remainder survive to become apparently normal adults. Embryonic death of PAR-1-null mice can be prevented by targeted expression of PAR-1 in endothelial cells. 13 Although PAR-1 is expressed by platelets and mediates platelet aggregation in humans, PAR-1 is not expressed by mouse platelets, and therefore is not required for normal blood coagulation in this species. 14 A number of models of bone repair have been established for use in mice, including an unstabilized fracture model, stabilized fracture models involving internal or external fi...

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“…A unifying explanation for these collective defects strongly implicated thrombin-generating proteases in the maintenance of (endothelial cell) vascular wall integrity, a hypothesis which was con®rmed by targeted expression of PAR1 to the vascular endothelial compartment of PAR1 null mice. Such a strategy rescued the lethal phenotype, with evidence for normal vascular development, and resolution of the abnormal bleeding causally implicated in intrauterine death [16]. Thus, loss of PAR1 signaling in endothelial cells probably explains the death at midgestation seen with knockout of tissue factor, FV, prothrombin (and possibly FX).…”

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confidence: 99%

Thrombin's faces revealed: cellular effects include induction of neoangiogenesis

Bahou

2003

Journal of Thrombosis and Haemostasis

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A Role for Thrombin Receptor Signaling in Endothelial Cells During Embryonic Development

Cited by 258 publications

References 20 publications

p45NF-E2 represses Gcm1 in trophoblast cells to regulate syncytium formation, placental vascularization and embryonic growth

p45NF-E2 represses Gcm1 in trophoblast cells to regulate syncytium formation, placental vascularization and embryonic growth

The Role of Protease-Activated Receptor-1 in Bone Healing

Thrombin's faces revealed: cellular effects include induction of neoangiogenesis

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