Cholesterol Inhibits H 2 S‐Mediated Vasodilation

Hydrogen sulfide (H 2 S), the most recently described endothelium‐derived vasodilator, is predominantly produced in the endothelium by cystathionine γ‐lyase (CSE). We previously demonstrated that within endothelial cells (ECs), H 2 S‐mediated vasodilation involves activation of transient receptor potential cation channel subfamily V member 4 (TRPV4)‐dependent Ca 2+ influx and large conductance Ca 2+ ‐activated potassium (BK) channel. In addition, a single concentration of H 2 S donor NaHS (1 μM) dilated small mesenteric arteries (<100 μm) but had no effect in large mesenteric arteries (>300 μm). Furthermore, inhibiting CSE generation of H 2 S with β‐cyanoalanine (BCA, 100 μM) impaired acetylcholine (ACh)‐induced dilation in small mesenteric arteries, but had no effect in large mesenteric arteries. These data suggest that H 2 S‐induced dilation is prominent and important in small resistance arteries but not in larger arteries. It is possible that decreased availability of TRPV4 and/or BK in larger arteries is responsible for the diminished sensitivity to H 2 S‐induced vasodilation. Previous reports suggest that membrane cholesterol negatively regulates TRPV4 mobility and BK activity. Our current study tested the hypothesis that H 2 S‐mediated vasodilation is inhibited by membrane cholesterol. Mesenteric arteries induced vasodilation was assessed in pressurized large rat mesenteric arteries (>300 μm). Isolated pressurized mesenteric arteries (320 μm – 360 μm) were pretreated luminally with vehicle (HEPES) or the cholesterol‐depleting agent, methyl β cyclodextran (MBCD, 100 μM) and exposed to NaHS (100 μM). NaHS‐induced dilation in U46619 pre‐constricted arteries was significantly enhanced by MBCD pretreatment (+vehicle: 6.78% ± 1.6, +MBCD: 17.10% ± 6.8, p < 0.05, n=3–4 animals/group). These studies suggest that membrane cholesterol disrupts H 2 S‐mediated vasodilation. Ongoing studies in isolated mesenteric arteries of different sizes are investigating endothelial cell membrane cholesterol content and the effect of cholesterol depletion on TRPV4‐dependent Ca 2+ influx in large and small mesenteric arteries. Support or Funding Information Funding provided by the NIH HL12330 & HL7736‐23 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .