Crosstalk between BMP signaling and KCNK3 in phenotypic switching of pulmonary vascular smooth muscle cells
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Pulmonary arterial hypertension (PAH) is a progressive and devastatingdisease whose pathogenesis is associated with a phenotypicswitch of pulmonary arterial vascular smooth muscle cells(PASMCs). Bone morphogenetic protein (BMP) signaling andpotassium two pore domain channel subfamily K member 3(KCNK3) play crucial roles in PAH pathogenesis. However, therelationship between BMP signaling and KCNK3 expression inthe PASMC phenotypic switching process has not been studied. In this study, we explored the effect of BMPs on KCNK3 expressionand the role of KCNK3 in the BMP-mediated PASMCphenotypic switch. Expression levels of BMP receptor 2 (BMPR2)and KCNK3 were downregulated in PASMCs of rats with PAHcompared to those in normal controls, implying a possibleassociation between BMP/BMPR2 signaling and KCNK3 expressionin the pulmonary vasculature. Treatment with BMP2, BMP4,and BMP7 significantly increased KCNK3 expression in primaryhuman PASMCs (HPASMCs). BMPR2 knockdown and treatmentwith Smad1/5 signaling inhibitor substantially abrogated theBMP-induced increase in KCNK3 expression, suggesting thatKCNK3 expression in HPASMCs is regulated by the canonicalBMP-BMPR2-Smad1/5 signaling pathway. Furthermore, KCNK3knockdown and treatment with a KCNK3 channel blocker completelyblocked BMP-mediated anti-proliferation and expressionof contractile marker genes in HPAMSCs, suggesting that theexpression and functional activity of KCNK3 are required forBMP-mediated acquisition of the quiescent PASMC phenotype. Overall, our findings show a crosstalk between BMP signalingand KCNK3 in regulating the PASMC phenotype, whereinBMPs upregulate KCNK3 expression and KCNK3 then mediatesBMP-induced phenotypic switching of PASMCs. Our resultsindicate that the dysfunction and/or downregulation of BMPR2and KCNK3 observed in PAH work together to induce aberrantchanges in the PASMC phenotype, providing insights into thecomplex molecular pathogenesis of PAH.
Abstract
Pulmonary arterial hypertension (PAH) is a progressive and devastatingdisease whose pathogenesis is associated with a phenotypicswitch of pulmonary arterial vascular smooth muscle cells(PASMCs). Bone morphogenetic protein (BMP) signaling andpotassium two pore domain channel subfamily K member 3(KCNK3) play crucial roles in PAH pathogenesis. However, therelationship between BMP signaling and KCNK3 expression inthe PASMC phenotypic switching process has not been studied. In this study, we explored the effect of BMPs on KCNK3 expressionand the role of KCNK3 in the BMP-mediated PASMCphenotypic switch. Expression levels of BMP receptor 2 (BMPR2)and KCNK3 were downregulated in PASMCs of rats with PAHcompared to those in normal controls, implying a possibleassociation between BMP/BMPR2 signaling and KCNK3 expressionin the pulmonary vasculature. Treatment with BMP2, BMP4,and BMP7 significantly increased KCNK3 expression in primaryhuman PASMCs (HPASMCs). BMPR2 knockdown and treatmentwith Smad1/5 signaling inhibitor substantially abrogated theBMP-induced increase in KCNK3 expression, suggesting thatKCNK3 expression in HPASMCs is regulated by the canonicalBMP-BMPR2-Smad1/5 signaling pathway. Furthermore, KCNK3knockdown and treatment with a KCNK3 channel blocker completelyblocked BMP-mediated anti-proliferation and expressionof contractile marker genes in HPAMSCs, suggesting that theexpression and functional activity of KCNK3 are required forBMP-mediated acquisition of the quiescent PASMC phenotype. Overall, our findings show a crosstalk between BMP signalingand KCNK3 in regulating the PASMC phenotype, whereinBMPs upregulate KCNK3 expression and KCNK3 then mediatesBMP-induced phenotypic switching of PASMCs. Our resultsindicate that the dysfunction and/or downregulation of BMPR2and KCNK3 observed in PAH work together to induce aberrantchanges in the PASMC phenotype, providing insights into thecomplex molecular pathogenesis of PAH.
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