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.