Functional cooperation between IK Ca and TRPC1 channels regulates serum-induced vascular smooth muscle cell proliferation via mediating Ca 2+ influx and ERK1/2 activation.

The increased proliferation of vascular smooth muscle cells (VSMCs) contributes to the pathogenesis of vascular diseases. The intermediate conductance calcium-activated potassium (IK Ca ) channel plays a critical role in VSMC proliferation by raising the intracellular calcium concentration ([Ca 2+ ] i ), but the underlying mechanism is still not unclear. Here we investigated the cooperation between IK Ca and transient receptor potential canonical 1 (TRPC1) channels in mediating extracellular Ca 2+ entry, which in turn activates downstream Ca 2+ signalling in the regulation of VSMC proliferation using serum-induced cell proliferation model. Serum-induced cell proliferation was accompanied with up-regulation of IK Ca expression and an increase in [Ca 2+ ] i . Serum-induced cell proliferation and increase in [Ca 2+ ] i were suppressed by IK Ca inhibition with TRAM-34 or IK Ca knockdown. Serum-induced cell proliferation was strongly reduced by the removal of extracellular Ca 2+ with EGTA or intracellular Ca 2+ with BAPTA-AM and, additionally, by TRPC1 knockdown. Moreover, the increase in [Ca 2+ ] i induced by serum or by IK Ca activation with 1-EBIO was attenuated by TRPC1 knockdown. Finally, serum induced ERK1/2 activation, which was attenuated by treatment with TRAM-34 or BAPTA-AM, as well as TRPC1 knockdown. Consistently, serum-induced cell proliferation was suppressed by ERK1/2 inhibition with PD98059. Taken together, these results suggest that the IK Ca and TRPC1 channels cooperate in mediating Ca 2+ influx that activates the ERK1/2 pathway to promote cell proliferation, thus providing new mechanistic insights into VSMC proliferation.