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Updated: May 23, 2025

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Independent and synergistic roles of MEK-ERK1/2 and PKC pathways in regulating functional changes in vascular tissue

Spyridoula Kazantzi1,2, Lars Edvinsson3, Kristian Agmund Haanes1,2,4

  • 1Sensory Biology Unit, Translational Research Centre, Copenhagen University Hospital - Rigshospitalet, Glostrup, Denmark.

Journal of Molecular and Cellular Cardiology Plus
|May 21, 2025
PubMed
Abstract

Insights

Inhibition of MEK and PKC pathways independently impacts vascular function. Combined inhibition shows additive effects, with MEK effective early and PKC effective later in flow cessation models.

Area of Science:

  • Vascular Biology and Physiology
  • Molecular Signaling Pathways
  • Cardiovascular Research

Background:

  • The interplay between MEK-ERK1/2 and Protein Kinase C (PKC) pathways is crucial for tissue function but poorly understood.
  • Vascular tissue serves as an excellent model for studying these pathways, especially under conditions mimicking ischemia and cardiovascular diseases like flow cessation.
  • Understanding these pathways is key to developing targeted therapies for cardiovascular conditions.

Purpose of the Study:

  • To investigate the independent roles of MEK and PKC pathway inhibition on functional receptor upregulation in vascular tissue.
  • To determine the additive effects and time-dependent dynamics of inhibiting these pathways.
  • To elucidate the mechanisms underlying vascular functional changes following flow cessation.

Main Methods:

  • Rat basilar arteries were cultured and treated with selective inhibitors for MEK (Trametinib), PKC (RO-317549), ERK (Ulixertinib), and NF-kB (BMS 345541).
  • Functional assessment of Endothelin B (ETB) receptor responses was performed using wire myography after Sarafotoxin 6c (S6c) stimulation.
  • Western blot analysis was used to quantify ERK phosphorylation, and the timing and combination of inhibitor treatments were evaluated.

Main Results:

  • MEK inhibition decreased ERK phosphorylation and ETB receptor-mediated contractility.
  • PKC inhibition reduced ETB receptor function without affecting ERK phosphorylation.
  • Combined MEK and PKC inhibition demonstrated additive effects, leading to greater suppression of functional changes than single treatments. PKC inhibition was effective even when applied 6 hours after flow cessation, while MEK inhibition was less effective at this later time point.

Conclusions:

  • MEK and PKC pathways independently regulate functional changes in vascular tissue, particularly after flow cessation.
  • MEK pathway inhibition is most effective when applied early, whereas PKC pathway inhibition remains effective even when applied later.
  • The additive effects of combined inhibition suggest parallel and independent activation of these pathways during ETB receptor upregulation.
Keywords:
ETB upregulationFlow cessationIschemiaMEK-ERK1/2 pathwayPKC pathwayVasoconstriction

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