Crosstalk between thromboxane and bradykinin receptors in vascular smooth muscle cells -

Abstract

Vascular inflammation and atherosclerosis are currently major causes of morbidity and mortality. Upon vascular injury, Thromboxane (TX) and Bradykinin (BK) contribute to the exacerbation of vascular diseases by inducing proliferation and constriction of vascular smooth muscle cells (VSMCs) through activating their corresponding G-protein coupled receptors (GPCRs): TX receptor (TP) and BK type-2 receptor (B2R) respectively. Cell surface localization of each of B2R and TP on the plasma membrane of VSMCs has been individually demonstrated in previous studies. Other studies have also shed light on the individual capability of each of BK and TX to favor VSMCs proliferation by activating the mitogen activated protein kinase (MAPK) cascade. Although much is known about how stimulation of either B2R or TP could activate MAPK in isolation, to our knowledge, no previous work has been done addressing how MAPK activity is regulated when those receptors are activated simultaneously. Here, we investigated the crosstalk between B2R and TP in VSMCs. Our findings provide pharmacological evidence of cooperative activation of the ERK pathway when both TP and B2R were simultaneously activated. This cooperation was synergistic in BK-dependent modulation of TP mitogenic responses and additive in the inverse direction. We also found that this cooperation could be inhibited when VSMCs were pretreated with the TP antagonist, SQ29548. However, this reciprocal effect between B2R and TP could not be secondary to non-specific binding of IBOP (TP stable agonist) or SQ29548 to B2R as seen in HEK293T cells overexpressing B2R. On the other hand, this synergy could not be reverted by the B2R-selective antagonist, HOE140, which could be exerting a possible biased agonist signaling property on the ERK1-2 pathway during the cooperation between TP and B2R. Therefore, a possible physical interaction could be involved in the cross-modulation between TP and B2R and could thus account to the pharmacologically suggested synergy. Taking into account the