Tumor necrosis factor increases the sensitivity of the contractile apparatus in isolated mouse resistance arteries via a calcium-dependent mechanism

Introduction

The myogenic response is the modulation of resistance artery diameter in response to changes in luminal pressure. It is thought to be an important determinant of peripheral vascular resistance and therefore of arterial blood pressure. Since altered peripheral resistance is known to occur during the systemic inflammatory response syndrome (such as in sepsis), we suspect that an abnormal myogenic response might be responsible. Our main objective is to assess the effects of tumor necrosis factor alpha (TNF-α) on the myogenic response of mouse mesenteric resistance arteries and to determine the role of Ca²⁺ in this response.

Hypothesis

TNF-α reduces the myogenic response in mesenteric resistance arteries by reducing smooth muscle cell Ca²⁺ sensitivity.

Methods and results

Vessels (external diameter ~ 150–200 μm) were mounted on a pressure myograph and allowed to develop myogenic constriction. After endothelial cell removal, baseline measurements were obtained and measurements were repeated 1 hour after treatment with TNF-α (50 ng/ml). TNF-α resulted in reduced myogenic tone at increasing luminal pressures (see Fig. 1). To determine the role of Ca²⁺ in this response, the passive internal diameter was measured in a Ca²⁺-free solution. TNF-α significantly shifted the Ca²⁺–diameter relation to the right, as assessed by stepwise increasing of extracellular Ca²⁺ (0–1.5 mmol/l) in depolarized skeletal muscle resistance arteries. This suggests a decreased Ca²⁺ sensitization of the smooth muscle cell contractile apparatus.

Figure 1

(abstract P81)

Conclusion

We conclude that, in mouse mesenteric resistance arteries, TNF-α treatment results in reduced myogenic tone that may be due partly to decreased Ca²⁺ sensitivity. These results suggests that the microvascular dysfunction seen during sepsis could be due in part to a decreased myogenic response.