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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:1810.)
© 2004 American Heart Association, Inc.

Vascular Biology

ADP Receptor P2Y₁₂ Is Expressed in Vascular Smooth Muscle Cells and Stimulates Contraction in Human Blood Vessels

Anna-Karin Wihlborg; Lingwei Wang; Oscar Östberg Braun; Atli Eyjolfsson; Ronny Gustafsson; Tomas Gudbjartsson; David Erlinge

From the Departments of Cardiology (A.-K.W., L.W., O.O., D.E.) and Cardiothoracic Surgery (A.E., R.G., T.G.), Lund University, Sweden.

Correspondence to Dr David Erlinge, Department of Cardiology, Lund University Hospital, S-221 85 Lund, Sweden. E-mail david.erlinge{at}kard.lu.se

Objective— ADP plays an important role in platelet aggregation by activating P2Y₁₂ receptors. We assessed the hypothesis that P2Y₁₂ receptors are expressed in vascular smooth muscle cells (VSMC).

Methods and Results— P2Y₁₂ receptor mRNA was found to have a high expression among the P2 receptors in human VSMC, significantly higher than the other 2 ADP receptors (P2Y₁ and P2Y₁₃, real-time polymerase chain reaction). Western blots gave a band of 50 kD, similar to that in platelets. To unmask a P2Y₁₂ receptor-mediated vasoconstriction by simulating the in vivo situation, vessels were precontracted to a submaximal level. 2-MeSADP stimulated contractions in vessel segments from internal mammary artery (IM), IM branches and small veins (E_max=15±6% of 60mmol/L K⁺ contraction, pEC₅₀=5.6±0.6, E_max=21±1%, pEC₅₀=6.8±0.1, and E_max=48±9%, pEC₅₀=6.6±0.4). The selective P2Y₁₂ antagonist AR-C67085 blocked 2-MeSADP contractions. The contraction was not reduced in patients using clopidogrel, a drug inhibiting ADP-induced platelet aggregation by blocking the P2Y₁₂ receptor. This may be explained by the high instability of the active clopidogrel metabolite that never reaches the systemic circulation.

Conclusion— ADP acting on P2Y₁₂ receptors not only is important for platelet activation but also stimulates vasoconstriction. Stable drugs with antagonistic effects on P2Y₁₂ receptors, affecting both platelets and VSMC, could be of double therapeutic benefit in their prevention of both thrombosis and vasospasm.

ADP causes platelet aggregation by P2Y₁₂ receptor activation. We show that P2Y₁₂ is expressed on vascular smooth muscle cells, and also that it has contractile function. These results give rise to new aspects of P2Y₁₂-blocking drugs, such as having double therapeutic benefit in their prevention of thrombosis and vasospasm.

Key Words: vasoconstriction • P2Y receptors • platelets • ADP

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