Chronic Elevation of Endothelin-1 Alone May Not Be Sufficient to Impair Endothelium-Dependent Relaxation

Hypertension. 2019 Dec;74(6):1409-1419. doi: 10.1161/HYPERTENSIONAHA.119.13676. Epub 2019 Oct 21.

Abstract

Endothelin-1 (ET-1) is a powerful vasoconstrictor peptide considered to be causally implicated in hypertension and the development of cardiovascular disease. Increased ET-1 is commonly associated with reduced NO bioavailability and impaired vascular function; however, whether chronic elevation of ET-1 directly impairs endothelium-dependent relaxation (EDR) remains elusive. Herein, we report that (1) prolonged ET-1 exposure (ie, 48 hours) of naive mouse aortas or cultured endothelial cells did not impair EDR or reduce eNOS (endothelial NO synthase) activity, respectively (P>0.05); (2) mice with endothelial cell-specific ET-1 overexpression did not exhibit impaired EDR or reduced eNOS activity (P>0.05); (3) chronic (8 weeks) pharmacological blockade of ET-1 receptors in obese/hyperlipidemic mice did not improve aortic EDR or increase eNOS activity (P>0.05); and (4) vascular and plasma ET-1 did not inversely correlate with EDR in resistance arteries isolated from human subjects with a wide range of ET-1 levels (r=0.0037 and r=-0.1258, respectively). Furthermore, we report that prolonged ET-1 exposure downregulated vascular UCP-1 (uncoupling protein-1; P<0.05), which may contribute to the preservation of EDR in conditions characterized by hyperendothelinemia. Collectively, our findings demonstrate that chronic elevation of ET-1 alone may not be sufficient to impair EDR.

Keywords: NO synthase; aorta; blood pressure; humans; hypertension.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta / physiopathology
  • Blotting, Western / methods
  • Endothelial Cells / drug effects
  • Endothelin-1 / pharmacology*
  • Female
  • In Vitro Techniques
  • Mass Spectrometry / methods
  • Mice
  • Mice, Inbred C57BL
  • Models, Animal
  • Nitric Oxide / metabolism*
  • Sensitivity and Specificity
  • Vasoconstrictor Agents / pharmacology*
  • Vasodilation / drug effects*

Substances

  • Endothelin-1
  • Vasoconstrictor Agents
  • Nitric Oxide