Myogenic responsiveness (MR) is the property of resistance artery smooth muscle cells to oppose stretch through vasoconstriction. MR is the primary mechanism regulating peripheral resistance; its augmentation in heart failure (HF) compromises tissue perfusion. In cerebral arteries from HF mice, enhanced MR and reduced cerebral blood flow are governed by an autocrine effect of TNFα. Therefore, we hypothesize that (i) TNFα is an integral part of the mechano-sensitive chain (i.e., HF augments a physiological mechanism) and ii) TNFα drives augmented peripheral resistance in HF by augmenting skeletal muscle resistance artery (sRA) tone.

Sequestration of TNFα with etanercept (ETAN) reduced MR, intracellular [Ca²⁺], and MLC₂₀ phosphorylation in sRAs from four species (mouse, hamster, dog, and human). ETAN did not affect these parameters after boiling or in sRAs from TNFα^-/- mice. Exogenous TNFα and inhibition of the TNFα converting enzyme by TAPI-1 failed to affect MR in sRAs. These manipulations did not affect vasoreactivity to phenylephrine, norepinephrine, and acetylcholine. In fully established murine HF, ETAN corrected the augmented MR in sRAs. sRAs from TNFα^-/- HF mice did not show increased MR.

Our data suggest that TNFα is an essential component of the mechano-sensitive chain regulating MR in sRAs. This mechanism is conserved over four different species. The lack of a TAPI-1 or (exogenous) TNFα effects suggests a sensing mechanism independent of TNFα shedding. We propose that HF recruits this physiological mechanism to sustain the compensatory increase in peripheral resistance that stabilizes systemic blood pressure at the cost of tissue perfusion.