Cystathionine γ-Lyase Modulates Flow-Dependent Vascular Remodeling
Objective—Flow patterns differentially regulate endothelial cell phenotype, with laminar flow promoting vasodilation and disturbed flow promoting endothelial proinflammatory activation. CSE (cystathionine γ-lyase), a major source of hydrogen sulfide (H2S) in endothelial cells, critically regulates cardiovascular function, by both promoting vasodilation and reducing endothelial activation. Therefore, we sought to investigate the role of CSE in the endothelial response to flow.
Approach and Results—Wild-type C57Bl/6 and CSE knockout (CSE−/−) mice underwent carotid partial ligation to induce disturbed flow in the left carotid. In addition, endothelial cells isolated from wild-type and CSE−/− mice were exposed to either laminar or oscillatory flow, an in vitro model of disturbed flow. Interestingly, laminar flow significantly reduced CSE expression in vitro, and only disturbed flow regions show discernable CSE protein expression in vivo, correlating with enhanced H2S production in wild-type C57Bl/6 but not CSE−/− mice. Lack of CSE limited disturbed flow-induced proinflammatory gene expression (ICAM-1[intercellular adhesion molecule 1], VCAM-1 [vascular cell adhesion molecular 1]) and macrophage infiltration and CSE−/− endothelial cells show reduced NF-κB (nuclear factor–κB) activation and proinflammatory gene expression in response to oscillatory flow in vitro. In addition, CSE−/− mice showed reduced inward remodeling after carotid ligation. CSE−/− mice show elevated vascular nitrite levels (measure of nitric oxide [NO]) in the unligated carotids, suggesting an elevation in baseline NO production, and the NO scavenger c-PTIO normalized the reduced inward remodeling, but not inflammation, of ligated carotids in CSE−/− mice.
Conclusions—CSE expression in disturbed flow regions critically regulates both endothelial activation and flow-dependent vascular remodeling, in part through altered NO availability.
- Received December 13, 2017.
- Accepted June 20, 2018.
- © 2018 American Heart Association, Inc.