Antenatal Dexamethasone Exposure Impairs the High-Conductance Ca2+-Activated K+ Channels via Epigenetic Alteration at Gene Promoter in Male Offspring

Arterioscler Thromb Vasc Biol. 2020 Nov;40(11):e284-e295. doi: 10.1161/ATVBAHA.120.314905. Epub 2020 Sep 24.

Abstract

Objective: Antenatal exposure to glucocorticoids increases cardiovascular risks related to vascular dysfunctions in offspring, although underlying mechanisms are still unknown. As an important vascular mediator, high-conductance Ca2+-activated K+ channels (BK) plays an essential role in determining vascular tone. Long-term effects of antenatal glucocorticoids on BK in offspring are largely unknown. This study examined the effects and mechanisms of antenatal exposure to clinically relevant doses of glucocorticoids on vascular BK in offspring. Approach and Results: Pregnant Sprague-Dawley rats received synthetic glucocorticoids dexamethasone or vehicle during the last week of pregnancy. Vascular functions, cellular electrophysiology, target gene expression, and promoter methylation were examined in mesenteric arteries of male offspring (gestational day 21 [fetus] and postnatal day 120 [adult offspring]). Antenatal dexamethasone exposure impaired BK activators-mediated relaxation and reduced whole-cell BK currents in mesenteric arteries. Antenatal dexamethasone exposure did not alter Ca2+/voltage-sensitivity of BK but downregulated the expressions of BK α and β1 subunits in both fetal and adult mesenteric arteries. In addition, increased promoter methylations within BKα and BKβ1 were compatible with reduced expressions of the 2 genes.

Conclusions: Our findings showed a profound and long-term impact of antenatal dexamethasone exposure on vascular BK via an altered epigenetic pattern from fetal stage to adulthood, advancing understanding of prolonged adverse effects and mechanisms of antenatal glucocorticoids exposure on vascular health in offspring.

Keywords: adult; electrophysiology; glucocorticoids; mesenteric arteries; risk factor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials
  • Animals
  • DNA Methylation*
  • Dexamethasone / administration & dosage
  • Dexamethasone / toxicity*
  • Epigenesis, Genetic*
  • Female
  • Glucocorticoids / administration & dosage
  • Glucocorticoids / toxicity*
  • Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / genetics*
  • Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / metabolism
  • Large-Conductance Calcium-Activated Potassium Channel beta Subunits / genetics*
  • Large-Conductance Calcium-Activated Potassium Channel beta Subunits / metabolism
  • Male
  • Maternal Exposure
  • Mesenteric Arteries / metabolism*
  • Mesenteric Arteries / physiopathology
  • Pregnancy
  • Prenatal Exposure Delayed Effects*
  • Promoter Regions, Genetic*
  • Rats, Sprague-Dawley
  • Vasodilation

Substances

  • Glucocorticoids
  • KCNMB1 protein, rat
  • Kcnma1 protein, rat
  • Large-Conductance Calcium-Activated Potassium Channel alpha Subunits
  • Large-Conductance Calcium-Activated Potassium Channel beta Subunits
  • Dexamethasone