Female sex and Western-style diet protect mouse resistance arteries during acute oxidative stress

Abstract

A Western-style diet (WD; high in fat and carbohydrates) increases vascular oxidative stress. We hypothesized that vascular cells adapt to a WD by developing resilience to oxidative stress. Male and female C57BL/6J mice (4 wk of age) were fed a control diet (CD) or a WD for 16-20 wk. Superior epigastric arteries (SEAs; diameter, ~125 µm) were isolated and pressurized for study. Basal reactive oxygen species production was greatest in SEAs from males fed the WD. During exposure to H₂O₂ (200 μM, 50 min), propidium iodide staining identified nuclei of disrupted endothelial cells (ECs) and smooth muscle cells (SMCs). For mice fed the CD, death of SMCs (21%) and ECs (6%) was greater (<i>P</i> < 0.05) in SEAs from males than females (9% and 2%, respectively). WD consumption attenuated cell death most effectively in SEAs from males. With no difference at rest, H₂O₂ increased intracellular Ca²⁺ concentration ([Ca²⁺]_i) to the greatest extent in SEAs from males, as shown by fura 2 fluorescence. Selective disruption of the endothelium (luminal air bubble) increased [Ca²⁺]_i and SMC death during H₂O₂ exposure irrespective of sex; the WD reduced both responses most effectively in males. Nonselective transient receptor potential (TRP) channel inhibition (ruthenium red, 5 μM) attenuated the rise of [Ca²⁺]_i, as did selective inhibition of TRP vanilloid type 4 (TRPV4) channels (HC-067047, 1 μM), which also attenuated cell death. In contrast, inhibition of voltage-gated Ca²⁺ channels (diltiazem, 50 μM) was without effect. Thus, for resistance arteries during acute oxidative stress: <i>1</i>) ECs are more resilient than (and can protect) SMCs, <i>2</i>) vessels from females are inherently more resilient than those from males, and <i>3</i>) a WD increases vascular resilience by diminishing TRPV4 channel-dependent Ca²⁺ entry.