Objective: The increase in vascular resistance observed in heart failure primarily results from an enhanced myogenic response (MR), the intrinsic property of resistance arteries (RA) to adapt their diameter and hence, resistance, to changes in pressure. We have recently shown that the cytokine tumor necrosis factor a(TNFa) augments the MR by activating sphingosine kinase-1 (Sk1). We hypothesized that the TNFa-Sk1 axis also operates under physiological conditions and that TNFa is an integral signaling element underlying the MR. Methods: Isolated hamster RA (n=6) were cultured in a pressure myograph for 20hrs prior to functional tests. Results: Elevation of transmural pressure induced a robust MR (80±23% reversal of pressure-induced distension). The soluble TNFa receptor etanercept (ETAN; 10mg/mL), which sequesters TNFa, abrogated the MR. This result was confirmed in mouse cremaster RA (n=5). Constriction to norepinephrine (NE) and dilation to acetylcholine (ACh) remained unaffected by ETAN. Heat-inactivated ETAN (n=6) did not affect the MR or NE-/ACh-stimulated responses. TNFa increased Erk1/2 phosphorylation, which is tightly linked to Sk1 activation in resistance arteries. Conclusions: Our data suggest that: (i) TNFa is readily available in the artery wall, (ii) its activation is sensitive to changes in transmural pressure and (iii) TNFa is a key element of the signaling pathway that regulates the MR. Funding: Natural Sciences and Engineering Research Council of Canada, Heart & Stroke Foundation of Ontario, Canadian Institutes of Health Research