TBI sex dependently upregulates ET-1 to impair autoregulation, which is aggravated by phenylephrine in males but is abrogated in females

Abstract

Traumatic brain injury (TBI) contributes to morbidity in children, and boys are disproportionately represented. Endothelin-1 (ET-1) contributes to impaired autoregulation via oxygen (O₂⁻) after TBI in piglets, but its relative role in males compared with females has not been previously investigated. Increased cerebral perfusion pressure (CPP) via phenylephrine (Phe) sex dependently improves impairment of autoregulation after TBI through modulation of extracellular signal-related kinase (ERK) mitogen-activated protein kinase (MAPK) upregulation, aggravated in males, but blocked in females. Activation of adenosine-5'-triphosphate (ATP) and Ca sensitive K channels produce vasodilation, contributing to autoregulation. We hypothesized that ET-1 upregulation is greater in males after TBI and that disturbed autoregulation will be prevented by Phe in a sex-dependent manner through modulation of ET-1, O₂⁻, and ERK. Results show that ET-1 release was greater in males after fluid percussion injury (FPI), blunted by Phe in females, but aggravated in males. K channel vasodilation was impaired more in males than in females after TBI. Phe prevented reductions in K channel vasodilation in females, but further reduced dilation in males after TBI. Co-administration of BQ-123, U0126, or PEG-SOD (ET-1, ERK antagonist, and O₂⁻ scavenger) with Phe restored dilation to K agonists and hypotension in males after TBI. ERK upregulation was blocked by BQ-123 and PEG-SOD. These data indicate that TBI upregulates ET-1 more in males than in females. Elevation of CPP with Phe sex dependently prevents impairment of cerebral autoregulation after TBI through modulation of ET-1, O₂⁻, and ERK mediated impairment of K channel vasodilation. These observations advocate for the consideration of development of sex-based therapies for the treatment of hemodynamic sequelae of pediatric TBI.

FIG. 1.

Influence of fluid percussion injury (FPI) on cerebrospinal fluid (CSF) Endothelin-1 (ET-1) in (A) male and (B) female pigs. Conditions are: before (0 time) and 1 h after FPI; in vehicle (FPI), phenylephrine (Phe) pre- and post-treated animals. Pre-treatment is 30 min before whereas post-treatment is 30 min after FPI, n=5. *p<0.05 compared with corresponding before FPI value; ⁺p<0.05 compared with corresponding untreated FPI value; ^#p<0.05 compared with corresponding female value.

FIG. 2.

Influence of fluid percussion injury (FPI) on pial artery diameter during hypotension (moderate, severe) in (A) male and (B) female pigs. Conditions are: before (sham control) and 1 h after FPI; in vehicle (FPI), phenylephrine (Phe), and Phe+BQ-123 (1 mg/kg i.v.) pre- and post-treated animals. Pre-treatment is 30 min before whereas post-treatment is 30 min after FPI, n=5. *p<0.05 compared with corresponding before FPI value; ⁺p<0.05 compared with corresponding untreated FPI value; ^#p<0.05 compared with corresponding female value.

FIG. 3.

Influence of papaverine (10⁻⁸, 10⁻⁶ M) on pial artery diameter in the absence and presence of fluid percussion injury (FPI) in (A) male and (B) female pigs. Conditions are: before (sham control) and 1 h after FPI; in vehicle (FPI), phenylephrine (Phe), and Phe+BQ-123 (1 mg/kg i.v.) pre- and post-treated animals. Pre-treatment is 30 min before whereas post-treatment is 30 min after FPI, n=5. *p<0.05 compared with corresponding before FPI value; ⁺p<0.05 compared with corresponding untreated FPI value; ^#p<0.05 compared with corresponding female value.

FIG. 4.

Influence of fluid percussion injury (FPI) on pial artery diameter in response to cromakalim (10⁻⁸, 10⁻⁶ M) in (A) male and (B) female pigs, and NS 1619 (10⁻⁸, 10⁻⁶ M), also in (C) male and (D) female pigs. Conditions are: before (control) and 1 h after FPI; in vehicle (FPI), phenylephrine (Phe), and Phe+BQ-123 (1 mg/kg i.v.) pre- and post-treated animals. Pre-treatment is 30 min before whereas post-treatment is 30 min after FPI, n=5. *p<0.05 compared with corresponding before FPI value; ⁺p<0.05 compared with corresponding untreated FPI value; ^#p<0.05 compared with corresponding female value.

FIG. 5.

Influence of fluid percussion injury (FPI) on pial artery diameter in response to cromakalim (10⁻⁸, 10⁻⁶ M) in (A) male and (B) female pigs, and NS 1619 (10⁻⁸, 10⁻⁶ M), also in (C) male and (D) female pigs. Conditions are: before (control) and 1 h after FPI; in vehicle (FPI), phenylephrine (Phe), and SODCAT pre- and post-treated animals. Pre-treatment is 30 min before whereas post-treatment is 30 min after FPI, n=5. *p<0.05 compared with corresponding before FPI value; ⁺p<0.05 compared with corresponding untreated FPI value; ^#p<0.05 compared with corresponding female value.

FIG. 6.

Influence of fluid percussion injury (FPI) on cerebrospinal fluid (CSF) extracellular signal-related kinase (ERK) mitogen-activated protein kinase (MAPK) (expressed as percent of total) in (A) male and (B) female pigs. Conditions are: before (0 time) and 1 h after FPI; in vehicle (FPI), phenylephrine (Phe), SODCAT, BQ-123, and UO126 pre- and post-treated animals. Pre-treatment is 30 min before whereas post-treatment is 30 min after FPI, n=5. *p<0.05 compared with corresponding before FPI value; ⁺p<0.05 compared with corresponding untreated FPI value; ^#p<0.05 compared with corresponding female value.

FIG. 7.

Schematic depicting the effects of Phe on cerebral autoregulation during hypotension, and the roles of Endothelin-1(ET-1), extracellular signal-related kinase (ERK), mitogen-activated protein kinase (MAPK), and superoxide on such effects in male and female pigs. Arrow thickness reflects the relative degree to which this action occurs.