Endothelium-platelet interactions

Platelets communicates not only internally by different signaling pathways, but also with other blood cells in the circulation and the endothelium, to interact in hemostasis and inflammation. 

Fig. 6.3 Eicosanoids and Tumor-platelet interactions in metastasis and the role of 12-HETE in tumor cell extravasation. Studies have clearly shown that hematogenous route of metastasis spread of cancer cells, involves interactions with platelets. Tumor-platelet interactions and subsequent aggregation is critically controlled by a delicate balance between the level of endothelium derived PGI2 and platelet or tumor derived TXA2. Elevated TXA2 levels in the circulation can tip the balance towards platelet aggregation and tumor metastasis to distant organs, whereas increases in PGI2 levels can block this interaction preventing spread of cancer cells. Shown in this illustration is a schematic of a blood vessel, with metastatic tumor cells interacting with platelets. Interactions of tumor cells with platelets and endothelial cells have been demonstrated to induce 12(S)-HETE production, which leads to retraction of endothelial cell layers enabling metastatic tumor cells to extravasate and set up secondary colonies of metastasis...

Fig. 1.4 Schematic view of the neurovascular unit or module and some of its components. Circulating blood elements, endothelial cells, astrocytes, extracellular matrix, basal lamina, adjacent neurons, and pericytes. After ischemia, perturbations in neurovascular functional integrity initiate multiple cascades of injury. Upstream signals such as oxidative stress, together with neutrophil and/or platelet interactions with activated endothelium, upregulate MMPs, plasminogen activators, and other pro-...

The endothelium can interact with circulating platelets in at least two ways. First of all, products of the platelet release reaction (i.e. ADP and serotonin) have been shown to be potent stimulators of endothelium-derived relaxing factor (i.e. NO). The second mechanism involves a direct and potent... 

ICAM-1, ICAM-2) and vascular cell adhesion molecule (VCAM). Platelets are attracted to damaged endothelium where they adhere to prevent blood loss in a similar fashion to white blood cells, i.e. via adhesion molecule interactions, to form a clot (thrombus). 

Therapeutic irradiation is known to have multiple interactions with the vasculature of the irradiated tissue (12). Radiation has direct cytotoxic effects on the vascular endothelium, likely due to induction of oxidative injury. Radiation-induced injury stimulates inflammation and influx of inflammatory cells in addition to creating aprocoagulant state in the vascular space by the transcriptional induction of tissue factor with the subsequent activation of coagulation factors as well as von Willebrand factor and platelets. Experimental evidence suggests that the mechanism by which radiation initiates these responses is in part through the induction of cell-adhesion molecules including ICAM-1, E-selectin, and P-selectin and in part through local cytokine production and release (13). 

One important mechanism of serotonin elimination is the (re-) uptake, e.g. by platelets. Furthermore, serotonin is metabolized by monoaminox-idase to 5-hydroxyindoleacetaldehyde and, subsequently, by an aldehyde dehydrogenase to 5-hydroxyindolacetic acid. The vascular effects of serotonin are complex. The direct interaction with vascular smooth muscle induces a vasoconstriction, whereas the stimulation of 5-HT-receptors on the endothelium induces the release of vasorelaxant factors with a dilatation as a result. An intravenous application of serotonin increases the pressure in the pulmonary circulation. A continuous infusion results... 

There are multicellular interactions that are important in inflammatory processes and in vascular remodeling. Activated platelets induce endothelial cells to secrete chemokines and to express adhesion molecules, indicating that platelets could initiate an inflammatory (Table I) response of the vessel wall. Activated platelets promote leukocyte binding to inflamed or atherosclerotic lesions (27,28). Cell adhesion molecules (CAMs) are responsible for leukocyte-endothelium interactions. It plays a crucial role in inflammation and atherogenesis. Vascular CAM-1 (VCAM-I)and intracellular CAM-1 (ICAM-I) promote monocyte recruitment to sites of injury and constitute a critical step in inflammation and in atherosclerotic plaque development. TSP-1, a matricellular protein released in abundance from activated platelets and accumulated in sites of vascular injury, induces the expression of VCAM-1 and ICAM-1 on endothelium and significantly increases the monocyte attachment (29). 

Interaction and adhesion of biological surfaces are central considerations for other physiological conditions as well. Platelets, erythrocytes, the vascular endothelium and other tissues interact during thrombosis and hemostasis. Also, when erythrocytes come in contact with artificial surfaces, damage often occurs and blood trauma may result. Finally, the accumulation of cholesterol deposits on the interior walls of arteries is responsible for atherosclerosis. 

In the presence of aspirin, AA, EPA, and DHA are converted to form epi-lipoxins, lipoxins, and resolvins that, in turn, enhance the formation of eNO (3, 4, 96). Lipoxins possess potent anti-inflammatory actions (reviewed in References 3 and 4). In addition, NO not only blocks the interaction between leukocytes and the vascular endothelium during inflammation but also stimulates the formation of PGI2, a potent vasodilator and platelet anti-aggregator, from AA (97, 98). 

Thirdly, there are the selectins, a family of Ca Mependent carbohydrate-binding proteins which function to control leukocyte interactions with vascular endothelium (Tedder et al, 1995). There are three closely related members of the selectin family, namely L (leukocyte)-, P (platelet)-, and E (endothelial)-selectin. P-selectin is expressed in the Weibel-Palade bodies of endothelial cells and in the a-granules of platelets. It is rapidly mobilized to the sur ce of endothelial cells and platelets in response to a variety of inflammatory agents such as fiuombin, histamine, complement factors, fiee radicals and cytokines (Tedder et al, 1995). P-selectin mediates the adhesion of neutrophils and monocytes to activated platelets and endothelial cells. Platelets can be bound to the endothelium indirectly by adhering to leukocytes bound to the endothelium. 

Ware JA, Heistad DD. Platelet-endothelium interactions. NEngl JMed 328 628-635,1993. 

Weiss HI IhriOo VT, Vide WJ, Baumgartner HR Effect of aspirin and dipyridamole on die interaction of human platelets with sub-endothelium studies using dtrated and native blood. Huomb Haemost 45 136-141,1981. 

The nitrates act by releasing nitric oxide, which relaxes vascular smooth muscle. The discovery that endothelium-derived relaxing factor (EDRF) is nitric oxide (1) stimulated new interest in these drugs, as nitric oxide not only controls local vessel wall tension in response to shear stress, but also plays a role in regulating the interaction of platelets with blood vessel walls. The release of nitric oxide from the walls of atheromatous arteries is reduced, because of malfunctioning or absent endothelium. Atheromatous arteries behave differently from healthy arteries, in that these vessels vasoconstrict rather than vasodilate when stimulated by acetylcholine. This impairment of the acetylcholine vasomotor response appears to be related to serum cholesterol concentration (2). 

Figure 15. Dose dependently c-GMP inhibits PDE or activates PKG, thereby mediating its effects on the vasculature, platelets and myocytes. The cardiac interstitial NO concentration during early ischemia and early reperfusion is increased. The increase in NO concentration is derived from activated NO synthase (NOS) isoforms (species specific) and from NOS independent pathways. Cardiac c-GMP concentration during ischemia is somewhat increased while upon reperfusion is decreased. NO seems to mediate protective as well as deleterious effects which are critically dependent on the specific experimental conditions. NO at lower concentrations preserves blood flow and attenuates platelet aggregation and neutrophil-endothelium interaction following ischemia and reperfusion. In small amounts might also be beneficial by nitration of the cardioprotective PKCe. Furthermore, NO increases cardiomyocyte function. Figure 16. At higher concentrations, NO depresses cardiomyocyte function, mediates inflammatory processes following ischemia and reperfusion, impairs mitochondrial respiration...

In conclusion, the Folts model of cyclic coronary blood flow variations clearly involves platelet microembolization. However, the role of physical obstruction versus microvascular constriction in the impaired myocardial perfusion is not entirely clear. Platelet-endothelium and platelet-leukocyte interactions may also contribute to the local inflammatory response37. 

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