Macrophages Cause Reduced Biosynthesis of Hydrogen Sulfide in the Obese Microvasculature

Obesity is associated with recruitment of macrophages to the microvascular adventitia. The current objective was to define how macrophage‐derived signals contribute to microvascular dysfunction. Based on recent findings that impaired H 2 S signaling is associated with cardiovascular pathologies, it was hypothesized that in the diet‐induced mouse model of obesity microvascular H 2 S is depleted by a mechanism that involves interactions with perivascular macrophages. Mesenteric arterioles were isolated from 30 week‐old lean and obese mice and mounted for pressure myography. Vessels were loaded with the H 2 S indicator SF7‐AM and imaged using confocal microscopy. Obesity was associated with lower H 2 S levels in both the smooth muscle and endothelial layers. Generation of H 2 S is dependent on the substrate L‐cysteine and the enzyme cystathionine gamma‐lyase (CSE). Expression of CSE was not changed by obesity; however, L‐cysteine was less effective in evoking H 2 S production in these vessels, and was correlated with reduced relaxation when pre‐contracted with phenylephrine. Co‐culturing arterioles from lean mice overnight with peritoneal macrophages from obese mice resulted in vessel H 2 S depletion. In contrast, co‐culture of vessels from either lean or obese mice with macrophages from lean controls had no effects on vessel H 2 S. Taken together, these data support a model in which H 2 S biosynthesis is compromised in the obese microvasculature by a mechanism dependent on crosstalk with perivascular macrophages. Supported by the American Heart Association and a Chicago Medical School/Advocate Lutheran General Hospital Pilot Grant.