Abstract
Complex interactions between platelets and activated endothelium occur during the thrombo-inflammatory reaction at sites of vascular injuries and during vascular hemostasis. The endothelial receptor endoglin is involved in inflammation through integrin-mediated leukocyte adhesion and transmigration; and heterozygous mutations in the endoglin gene cause hereditary hemorrhagic telangiectasia type 1. This vascular disease is characterized by a bleeding tendency that is postulated to be a consequence of telangiectasia fragility rather than a platelet defect, since platelets display normal functions in vitro in this condition. Here, we hypothesize that endoglin may act as an adhesion molecule involved in the interaction between endothelial cells and platelets through integrin recognition. We find that the extracellular domain of human endoglin promotes specific platelet adhesion under static conditions and confers resistance of adherent platelets to detachment upon exposure to flow. Also, platelets adhere to confluent endothelial cells in an endoglin-mediated process. Remarkably, Chinese hamster ovary cells ectopically expressing the human αIIbβ3 integrin acquire the capacity to adhere to myoblast transfectants expressing human endoglin, whereas platelets from Glanzmann’s thrombasthenia patients lacking the αIIbβ3 integrin are defective for endoglin-dependent adhesion to endothelial cells. Furthermore, the bleeding time, but not the prothrombin time, is significantly prolonged in endoglin-haplodeficient (Eng+/−) mice compared to Eng+/+ animals. These results suggest a new role for endoglin in αIIbβ3 integrin-mediated adhesion of platelets to the endothelium, and may provide a better understanding on the basic cellular mechanisms involved in hemostasis and thrombo-inflammatory events.
Highlights
Endoglin (Eng; CD105) is a transmembrane glycoprotein, which is expressed by endothelial cells (EC), but not by platelets, and plays a critical physiological role in the cardiovascular system [1,2,3]
In search for counter-receptor(s) on platelets that could interact with endothelial endoglin, and given that we have previously demonstrated that the endoglin RGD motif is involved in integrin-mediated cell adhesion to EC [27, 28], we focused our attention on the αIIbβ3 integrin, a major RGD-dependent adhesive receptor in platelets [17, 25]
Intricate interactions between circulating platelets and an activated microvascular endothelium are at the basis of the thrombo-inflammatory reaction seen at sites of vascular injuries accompanying many pathophysiological situations [13, 20], and are likely an early step during vascular hemostasis [23, 24]
Summary
Endoglin (Eng; CD105) is a transmembrane glycoprotein, which is expressed by endothelial cells (EC), but not by platelets, and plays a critical physiological role in the cardiovascular system [1,2,3]. It is an auxiliary receptor for the transforming growth factor β (TGF-β) family of proteins and has been shown to be essential for angiogenesis [4, 5]. The pathophysiological importance of endoglin in vascular biology is clearly established in humans by the linkage between heterozygous mutations in the endoglin gene and. More than 500 different pathogenic mutations in endoglin have been reported, concerning up to 59% of the HHT patient population, defined as the HHT1 subtype [9]
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