Opioids Cause Sex-Specific Vascular Changes via Cofilin-Extracellular Signal-Regulated Kinase Signaling: Female Mice Present Higher Risk of Developing Morphine-Induced Vascular Dysfunction than Male Mice

J Vasc Res. 2021;58(6):392-402. doi: 10.1159/000517555. Epub 2021 Sep 14.


Recent studies have shown that chronic use of prescription or illicit opioids leads to an increased risk of cardiovascular events and pulmonary arterial hypertension. Indices of vascular age and arterial stiffness are also shown to be increased in opioid-dependent patients, with the effects being more marked in women. There are currently no studies investigating sex-specific vascular dysfunction in opioid use, and the mechanisms leading to opioid-induced vascular damage remain unknown. We hypothesized that exposure to exogenous opioids causes sex-specific vascular remodeling that will be more pronounced in female. Acknowledging the emerging roles of cofilins and extracellular signal-regulated kinases (ERKs) in mediating actin dynamics, we investigated the effects of morphine on these molecules. Twenty-four hour exposure to morphine increased inactivated cofilin and activated ERKs in resistance arteries from female mice, which may promote stress fiber over-assembly. We also performed continuous intraluminal infusion of morphine in pressurized resistance arteries from male and female mice using culture pressure myographs. We observed that morphine reduced the vascular diameter in resistance arteries from female, but not male mice. These results have significant implications for the previously unexplored role of exogenous opioids as a modifiable cardiovascular risk factor, especially in women.

Keywords: Opioids; Sex differences; Vascular physiology.

Publication types

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

MeSH terms

  • Actin Depolymerizing Factors / metabolism*
  • Analgesics, Opioid / toxicity*
  • Animals
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Female
  • Hemodynamics / drug effects*
  • Male
  • Mesenteric Arteries / drug effects*
  • Mesenteric Arteries / enzymology
  • Mesenteric Arteries / pathology
  • Mesenteric Arteries / physiopathology
  • Mice, Inbred C57BL
  • Morphine / toxicity*
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / metabolism
  • Muscle, Smooth, Vascular / pathology
  • Muscle, Smooth, Vascular / physiopathology
  • Myocytes, Smooth Muscle / drug effects
  • Myocytes, Smooth Muscle / metabolism
  • Myocytes, Smooth Muscle / pathology
  • Phosphorylation
  • Rats, Sprague-Dawley
  • Sex Factors
  • Signal Transduction
  • Vascular Remodeling / drug effects*


  • Actin Depolymerizing Factors
  • Analgesics, Opioid
  • Morphine
  • Extracellular Signal-Regulated MAP Kinases