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

Abstract

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.

Prenatal Morphine Exposure Increases Cardiovascular Disease Risk and Programs Neurogenic Hypertension in the Adult Offspring

“…Similarly, Cheon et al reported that female mice showed a greater risk of morphine-induced vascular dysfunction, increased arterial stiffness, and resistance via the cofilin-ERK signaling pathway, suggesting that impaired endothelial function may contribute to the high blood pressure in female rats along with sympathetic activation. 73 Taken together, the results from our study provide evidence that prenatal exposure to exogenous opioids may alter the programming and sensitivity of the vasculature to Ang II in a sex-specific manner. Although the circulating levels of RAS components were similar between vehicle and morphine-exposed rats, because of the discrepancy between in vivo and ex vivo responses, differences in RAS peptides at the central nervous system level cannot be ruled out.…”