Complex Formation between VEGFR2 and the β-Adrenoceptor.

Vascular endothelial growth factor (VEGF) is an important mediator of endothelial cell proliferation and angiogenesis via its receptor VEGFR2. A common tumor associated with elevated VEGFR2 signaling is infantile hemangioma that is caused by a rapid proliferation of vascular endothelial cells. The current first-line treatment for infantile hemangioma is the β-adrenoceptor antagonist, propranolol, although its mechanism of action is not understood.

How does measurement of platelet P-selectin compare with other methods of measuring platelet function as a means of determining the effectiveness of antiplatelet therapy?

Measurement of P-selectin on activated platelets as a means of measuring platelet function utilizing the technology described here has the advantage of not requiring immediate access to specialist equipment and expertise. Blood samples are activated, fixed, stored, and transported to a central laboratory for flow cytometric analysis. Here we have compared P-selectin with other more traditional approaches to measuring platelet function in blood and/or platelet-rich plasma (PRP) from patients with acute coronary syndromes on treatment for at least 1 month with either aspirin and clopidogrel or aspirin with prasugrel.

P2Y₁₂ and EP3 antagonists promote the inhibitory effects of natural modulators of platelet aggregation that act via cAMP.

Several antiplatelet drugs that are used or in development as antithrombotic agents, such as antagonists of P2Y₁₂ and EP3 receptors, act as antagonists at G(i)-coupled receptors, thus preventing a reduction in intracellular cyclic adenosine monophosphate (cAMP) in platelets. Other antiplatelet agents, including vascular prostaglandins, inhibit platelet function by raising intracellular cAMP. Agents that act as antagonists at G(i)-coupled receptors might be expected to promote the inhibitory effects of agents that raise cAMP.

Adenosine derived from ADP can contribute to inhibition of platelet aggregation in the presence of a P2Y12 antagonist.

Objective: To investigate whether adenosine diphosphate (ADP)-derived adenosine might inhibit platelet aggregation, especially in the presence of a P2Y₁₂ antagonist, where the effects of ADP at the P2Y₁₂ receptor would be prevented.

Methods And Results: Platelet aggregation was measured in response to thrombin receptor activator peptide by platelet counting in platelet-rich plasma (PRP) and whole blood in the presence of ADP and the P2Y₁₂ antagonists cangrelor, prasugrel active metabolite, and ticagrelor. In the presence of a P2Y₁₂ antagonist, preincubation of PRP with ADP inhibited aggregation; this effect was abolished by adenosine deaminase.

PGE1 and PGE2 modify platelet function through different prostanoid receptors.

There is evidence that the overall effects of prostaglandin E(2) (PGE(2)) on human platelet function are the consequence of a balance between promotory effects of PGE(2) acting at the EP3 receptor and inhibitory effects acting at the EP4 receptor, with no role for the IP receptor. Another prostaglandin that has been reported to affect platelet function is prostaglandin E(1) (PGE(1)), however the receptors that mediate its actions on platelet function have not been fully defined. Here we have used measurements of platelet aggregation and P-selectin expression induced by the thromboxane A(2) mimetic U46619 to compare the effects of PGE(1) and PGE(2) on platelet function.

Mode of action of P2Y(12 ) antagonists as inhibitors of platelet function.

P2Y(12) receptor antagonists are antithrombotic agents that inhibit platelet function by blocking the effects of adenosine diphosphate (ADP) at P2Y (12)receptors. However, some P2Y(12) receptor antagonists may affect platelet function through additional mechanisms. It was the objective of this study to investigate the possibility that P2Y(12) antagonists inhibit platelet function through interaction with G-protein-coupled receptors other than P2Y(12) receptors.

The role of prostanoid receptors in mediating the effects of PGE(2) on human platelet function.

The effects of prostaglandin E(2) (PGE(2)) on platelet function are believed to be the result of opposing mechanisms that lead to both enhancement and inhibition of platelet function. Enhancement of platelet function is known to be via EP3 receptors linked to G(i) and inhibition of adenylyl cyclase. However, the receptors involved in inhibition of platelet function have not been fully defined.

DG-041 inhibits the EP3 prostanoid receptor--a new target for inhibition of platelet function in atherothrombotic disease.

Receptors for prostanoids on platelets include the EP3 receptor for which the natural agonist is the inflammatory mediator prostaglandin E(2) (PGE(2)) produced in atherosclerotic plaques. EP3 is implicated in atherothrombosis and an EP3 antagonist might provide atherosclerotic lesion-specific antithrombotic therapy. DG-041 (2,3-dichlorothiophene-5-sulfonic acid, 3-[1-(2,4-dichlorobenzyl)-5-fluoro-3-methyl-1H-indol-7-yl]acryloylamide) is a direct-acting EP3 antagonist currently being evaluated in Phase 2 clinical trials.