Selective Inhibition of Tumor Necrosis Factor Signaling Alters Resistance Artery Myogenic Tone in Mice.

Objective In cardiovascular disease, tumor necrosis factor (TNF) enhances myogenic vascular responses, which can be counteracted by inhibition of membrane-bound TNF (tmTNF) and soluble TNF (solTNF). We hypothesized that the selective inhibition of solTNF can reduce myogenic responses in resistance arteries and, if so, may reduce systemic arterial blood pressure. Methods Second-order mesenteric arteries from adult C57BL/6J mice of both sexes were mounted in a pressure myograph. The effect of selective (XPro1595) and non-selective (etanercept (ETN)) TNF inhibitors on myogenic responses to incremental pressure (20–160 mmHg) was determined. Arterial blood pressure was measured in male C57BL/6J mice through indwelling femoral catheters coupled with a pressure monitor before and after the continuous infusion of XPro1595 in increasing doses (0.5, 1, and 2 mg/kg/day) followed by co-infusion with angiotensin II (ANGII, 60 ng/kg/min) or initial ANGII infusion followed by XPro1595 co-infusion (20 mg/kg/day). The long-term (2 months) effects of ETN (10mg/kg/third day) or XPro1595 (10 mg/kg/third day) treatment were determined based on morphological changes in the aortic and mesenteric medial areas in mice. Results XPro1595 eliminated myogenic tone in mesenteric arteries (males: p < 0.01, n = 11; females: p = 0.002, n = 6), while ETN (p = 0.03) was only effective in male mice. Mesenteric arteries from ANGII-induced hypertensive mice (n = 5–6), with or without XPro1595 treatment for 4 days, did not alter the myogenic response to incremental pressure changes or TNF exposure. XPro1595 did not impact baseline mean arterial pressure (MAP) or the development of ANGII-induced hypertension (n = 5–6). In established ANGII-induced hypertension, XPro1595 did not alter MAP (n = 6–8). In addition, XPro1595 or ETN treatment for two months did not affect the medial area, and media to lumen ratio in thoracic aorta or mesenteric arteries. Conclusion These results suggest that although solTNF contributed to myogenic responsiveness in mesenteric resistance arteries, it did not affect arterial blood pressure. Thus, we anticipate that the long-term treatment of inflammatory conditions with selective solTNF inhibitors, such as XPro1595, will not affect systemic arterial blood pressure regulation.