Diminished Rbfox1 increases vascular constriction by dynamically regulating alternative splicing of CaV1.2 calcium channel in hypertension.

Calcium influx from depolarized Ca_V1.2 calcium channels triggers the contraction of vascular smoothmuscle cells (VSMCs), which is important formaintaining vascular myogenic tone and blood pressure. The function of Ca_V1.2 channel can be subtly modulated by alternative splicing (AS), and its aberrant splicing involves in the pathogenesis ofmultiple cardiovascular diseases. The RNA-binding protein Rbfox1 is reported to regulate the AS events of Ca_V1.2 channel in the neuronal development, but its potential roles in vascular Ca_V1.2 channels and vasoconstriction remain undefined. Here, we detect Rbfox1 is expressed in rat vascular smooth muscles. Moreover, the protein level of Rbfox1 is dramatically decreased in the hypertensive small arteries from spontaneously hypertensive rats in comparison with normotensive ones from Wistar-Kyoto rats. In VSMCs, Rbfox1 could dynamically regulate the AS of Ca_V1.2 exons 9* and 33. By whole-cell patch clamp, we identify knockdown of Rbfox1 induces the hyperpolarization of Ca_V1.2 current--voltage relationship curve in VSMCs. Furthermore, siRNA-mediated knockdown of Rbfox1 increases the K⁺-induced constriction of rat mesenteric arteries. In summary, our results indicate Rbfox1 modulates vascular constriction by dynamically regulating Ca_V1.2 alternative exons 9* and 33. Therefore, our work elucidates the underlying mechanisms for Ca_V1.2 channels regulation and provides a potential therapeutic target for hypertension. [ABSTRACT FROM AUTHOR]