Functional cooperation between <scp>IK<sub>Ca</sub></scp> and <scp>TRPC1</scp> channels regulates serum‐induced vascular smooth muscle cell proliferation via mediating Ca<sup>2+</sup> influx and <scp>ERK1</scp>/2 activation
Xiaoling Jia, Xinlan Chen, Chao Gao, Haikun Wang, Chengxi Yang, Lin‐Hua Jiang, Yubo Fan
Abstract
Abstract 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.