Activated platelets induce Weibel-Palade–body secretion and leukocyte rolling in vivo: role of P-selectin

Abstract

The presence of activated platelets and platelet-leukocyte aggregates in the circulation accompanies major surgical procedures and occurs in several chronic diseases. Recent findings that activated platelets contribute to the inflammatory disease atherosclerosis made us address the question whether activated platelets stimulate normal healthy endothelium. Infusion of activated platelets into young mice led to the formation of transient platelet-leukocyte aggregates and resulted in a several-fold systemic increase in leukocyte rolling 2 to 4 hours after infusion. Rolling returned to baseline levels 7 hours after infusion. Infusion of activated P-selectin ؊/؊ platelets did not induce leukocyte rolling, indicating that platelet P-selectin was involved in the endothelial activation. The endothelial activation did not require platelet CD40L. Leukocyte rolling was mediated solely by the interaction of endothelial P-selectin and leukocyte P-selectin glycoprotein ligand 1 (PSGL-1 IntroductionPlatelets are the body's defense mechanism against excessive bleeding caused by endothelial damage. Activated platelets present at the site of injury provide both a prothrombotic surface and a procoagulant surface. Excessive platelet activation occurs in coronary bypass surgery and may result in thrombotic emboli and neurologic complications. 1 Furthermore, many inflammatory diseases including sepsis, 2,3 psoriasis, 4,5 diabetes, 6-8 and cystic fibrosis 9 are associated with circulating activated platelets. These pathologies are also associated with endothelial inflammation.Platelets induce leukocyte adhesion on preactivated endothelial cells in culture. 10,11 In mouse models of atherosclerosis, the role of activated platelets in exacerbating lesion development has been clearly demonstrated. Activated platelets promote monocyte arrest on atherosclerotic lesions and atherosclerotic lesion growth. 12 Studies in our laboratory have also demonstrated the role of platelet P-selectin, in addition to endothelial P-selectin, in atherosclerotic lesion development and maturation. 13 It is important to note that P-selectin on both platelets and endothelium is expressed on the cell surface only on activation of the cells and granule secretion. 14 Early endothelial inflammation is associated with the rapid release of Weibel-Palade bodies and the consequent surface expression of Pselectin and von Willebrand factor (VWF). These molecules mediate rolling of leukocytes and platelets on endothelial cells. 15 This is followed by transcription and expression of molecules such as E-selectin, vascular-cell adhesion molecule 1 (VCAM-1), and other adhesion receptors. 16 These receptors, in turn, mediate slow rolling and adhesion of leukocytes and have been shown to be up-regulated on treatment with activated platelets in the in vitro studies. [17][18][19][20] This sequence of events leads to leukocyte rolling and extravasation at the site of injury or pathologic conditions.Recently, vascular endothelial growth factor (VEGF) secreted from ␣-granules was sh...

CD40 Ligand Promotes Mac-1 Expression, Leukocyte Recruitment, and Neointima Formation after Vascular Injury

“…40 Immunohistochemical staining showed significant platelet deposition in the medial layer and on the luminal surface of the 1-day denudated carotid artery (see Supplemental Figure S1B, panel a, at http://ajp.amjpathol.org). P-selectin staining was restricted to the luminal surface (see Supplemental Figure S1B, panel b, at http://ajp.amjpathol.org), which is consistent with the known propensity of activated platelets to shed P-selectin 41 and supported by immunostaining data in a recent report. 42 These results suggest that activated platelets may provide an adhesive surface, mediating leukocyte rolling adhesion potentially through the interaction of P-selectin expressed on activated platelets with its ligand PSGL-1 expressed by leukocytes.…”

Novel Methods for Assessment of Platelet and Leukocyte Function Under Flow – Application of Epifluorescence and Two-Photon Microscopy in a Small Volume Flow Chamber Model

“…At high shear conditions, platelet adhesion to EC is a prerequisite for leukocyte adhesion, and inhibition of platelets adhesion with specific antibodies is accompanied by a significant reduction in the number of adherent leukocytes. These findings are well comparable to observations of leukocyte-endothelium-interactions in mice in vivo [28,29].…”

Radiation-Guided P-Selectin Antibody Targeted to Lung Cancer

“…These cell adhesion molecules are known for mediating leukocyte rolling on endothelial cells and platelet-leukocyte aggregation. 7,23,26 Studies have shown that elevated levels of selectins are present in the serum of subjects experiencing an inflammatory state. 30 P-selectin, in particular, is an important disease marker as it plays an essential role in many inflammatory processes including cancer, coronary artery disease, stroke, and diabetes.…”