Cholesterol Inhibits H₂S‐Mediated Vasodilation

Abstract

Hydrogen sulfide (H2S), 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), H2S‐mediated vasodilation involves activation of transient receptor potential cation channel subfamily V member 4 (TRPV4)‐dependent Ca2+ influx and large conductance Ca2+‐activated potassium (BK) channel. In addition, a single concentration of H2S 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 H2S 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 H2S‐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 H2S‐induced vasodilation. Previous reports suggest that membrane cholesterol negatively regulates TRPV4 mobility and BK activity. Our current study tested the hypothesis that H2S‐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 H2S‐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 Ca2+ influx in large and small mesenteric arteries.Support or Funding InformationFunding provided by the NIH HL12330 & HL7736‐23This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.