Background: Retinoid X receptors (RXR) are a family of nuclear receptors which play critical roles in the regulation of numerous fundamental biological processes including cell proliferation, differentiation and death. Earlier studies suggested that treatment with RXR agonists attenuate platelet activation in men and mice, however, the underlying molecular mechanisms have remained insufficiently understood.

Aims: To elaborate on the role of RXR in megakaryocytes and platelet.

Methods: We generated a megakaryocyte and platelet specific PF4Cre+;RXRbflox/flox conditional knock-out mice. We studies platelet activation and thrombopoiesis in the presence or absence of RXR ligands. Arterial thrombus was analysed in a Fe(III)Cl model in vivo.

Results: First, we identified RXRb as the dominant RXR receptor in murine platelets, prompting us to generate a megakaryocyte and platelet specific PF4^Cre;RXRb^flox/flox mouse. Second, we studied activation, spreading and aggregation of platelets from C57Bl/6 wild type mice (WT), PF4^Cre+;RXRb^flox/flox mice and PF4^Cre-;RXRb^flox/flox littermate controls in the presence or absence of RXR ligands, i.e. 9-cis-retinoic acid (9cRA) and methoprene acid (MA). We found that in vitro treatment with RXR ligands attenuates platelet spreading and aggregation response. In addition, an increase in megakaryocyte (MK) proplatelet particle formation was shown. However, these effects were also observed in RXRb-deficient platelets and MKs and thus are independent of RXRb. Next, we investigated arterial thrombus formation in a FeCl3-induced vascular injury model in vivo, which was not affected by the absence of RXRβ in platelets as well.

Conclusions: We found that absence of the most abundant RXR receptor in murine platelets, RXRβ, does not affect platelet function in vitro and thrombus formation in vivo. Furthermore, we showed that RXR agonists’ mediated effects on platelet function are independent of RXRβ expression. Hence, our data do not support a significant contribution of RXRβ to arterial thrombosis in mice.

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/role-of-rxrbeta-in-platelet-function-and-arterial-thrombosis/