Objective: Decreased cardiac output and a compensatory increase in total peripheral resistance (TPR) are hallmarks of heart failure (HF). The increase in TPR, which serves to maintain sufficient blood pressure levels, results from an upregulation of S1P signalling and hence, increased myogenic tone. We propose that HF is associated with the inhibition of cystic fibrosis transmembrane regulator (CFTR)-dependent S1P degrading mechanisms and that the downregulation of CFTR expression/activity represents the underlying molecular mechanism. Methods: We determined: (i) CFTR-dependent uptake of fluorescently-labelled S1P into VSMC via FACS; (ii) TNFa-mediated regulation of CFTR expression/activity via Immunoblot and immunostaining and (iii) expression/activity of CFTR in LAD ligated mice. Results: Primary VSMC isolated from mesenteric arteries of CFTR^+/+ showed rapid uptake of exogenously added S1P. This transmembrane transport of S1P was abolished following treatment with a CFTR inhibitor and absent in CFTR^-/- cells. The S1P import was rescued by transfection of wildtype CFTR. Incubation of VSMC with TNF significantly reduced CFTR expression, which resulted in a reduction of S1P uptake. In HF mice, which show specific enhancement of S1P-induced myogenic tone, TNFa levels in smooth muscle cells of the vascular wall were increased while expression of CFTR was significantly reduced. Conclusion: Our data indicate that CFTR is mandatory for the uptake and degradation of S1P in VSMC. Consequently, downregulation of CFTR, as seen in HF mice and following treatment with exogenous TNFa, reduces the degradation and enhances the availability of S1P. We propose that the downregulation of CFTR in HF mice enhances S1P signalling and therefore allows to sustain the increase in peripheral tone and hence, resistance.