Functional cooperation between IKCa and TRPC1 channels regulates serum‐induced vascular smooth muscle cell proliferation via mediating Ca2+ 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 (IKCa) channel plays a critical role in VSMC proliferation by raising the intracellular calcium concentration ([Ca2+]i), but the underlying mechanism is still not unclear. Here we investigated the cooperation between IKCa and transient receptor potential canonical 1 (TRPC1) channels in mediating extracellular Ca2+ entry, which in turn activates downstream Ca2+ signalling in the regulation of VSMC proliferation using serum‐induced cell proliferation model. Serum‐induced cell proliferation was accompanied with up‐regulation of IKCa expression and an increase in [Ca2+]i. Serum‐induced cell proliferation and increase in [Ca2+]i were suppressed by IKCa inhibition with TRAM‐34 or IKCa knockdown. Serum‐induced cell proliferation was strongly reduced by the removal of extracellular Ca2+ with EGTA or intracellular Ca2+ with BAPTA‐AM and, additionally, by TRPC1 knockdown. Moreover, the increase in [Ca2+]i induced by serum or by IKCa 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 IKCa and TRPC1 channels cooperate in mediating Ca2+ influx that activates the ERK1/2 pathway to promote cell proliferation, thus providing new mechanistic insights into VSMC proliferation. [ABSTRACT FROM AUTHOR]