Interleukin‐17 Impairs Cerebrovascular Function, Increases Blood‐Brain‐Barrier Permeability, and Induces Cerebral Edema in Pregnant Rats

Abstract

Cerebrovascular events account for ~40% of all preeclamptic/eclamptic‐related deaths and can induce neurological complications. While placental ischemia can impair cerebrovascular function in women with preeclampsia (PE) and rats which develop a PE‐like syndrome, the placental‐derived factors mediating these effects are elusive. Although pro‐inflammatory cytokines, including Interleukin‐17 (IL‐17), are increased by placental ischemia, it is not known whether IL‐17 disrupts cerebrovascular function during pregnancy. Therefore, we tested the hypothesis that infusion of IL‐17 during pregnancy impairs cerebral blood flow (CBF) autoregulation and myogenic tone, while also promoting increased regional blood‐brain‐barrier (BBB) permeability and brain water content (BWC). Pregnant Sprague Dawley rats were infused with recombinant IL‐17 (150 pg/day) via mini‐osmotic pump (i.p.) from gestational days 14–19. Cerebral blood flow was measured by laser Doppler flowmetry and myogenic tone was assessed in isolated middle cerebral arteries (MCA) by pressure‐flow myography. BWC was determined by quantifying dry:wet weight ratio and BBB permeability was measured by Evans blue extravasation. As previously shown, IL‐17 increased MAP (112 ± 2.5 vs 99.7 ± 2.8 mmHg; p<0.01) compared to pregnant control rats. CBF was significantly greater in IL‐17‐treated pregnant rats at 180 mmHg (187 ± 19 vs 149 ± 22%; p<0.05) and 190 mmHg (215 ± 18 vs 160 ± 23%; p<0.01) compared to pregnant control rats. Myogenic tone peaked at 125 mmHg in the MCA of IL‐17‐treated rats and declined thereafter, forming an inverted‐U curve in response to increases in intraluminal pressure. In contrast, myogenic tone peaked at 175 mmHg in control pregnant rats, forming a hyperbolic curve, which suggests that myogenic responses are blunted at high arterial pressures in IL‐17‐treated rats. BWC tended to increase in the cortex (80.5 ± 0.2 vs. 79.5 ± 0.4%, p = 0.054) and striatum (77.6 ± 0.8 vs. 75.1 ± 1.4%, p = 0.062), and was significantly increased in the posterior cerebrum (79.7 ± 0.4 vs. 77.8 ± 0.5%, p< 0.01) and cerebrum (79.8 ± 0.3 vs. 78.8 ± 0.1%, p< 0.01) of IL‐17‐treated rats. IL‐17 increased BBB permeability in the cortex only (0.017 ± 0.002 vs 0.012 ± 0.002, p<0.05). These data suggest that increases in circulating IL‐17 during pregnancy could contribute to cerebrovascular dysfunction leading to impaired CBF control and myogenic responses, cerebral edema, and increased BBB permeability. IL‐17 may be a potential therapeutic target to prevent or ameliorate neurological impairment in preeclampsia. Future studies examining whether blockade of IL‐17 in placental ischemic rats could prevent cerebrovascular dysfunction may provide valuable insight into the role of cytokines on cerebrovascular health during pregnancy.Support or Funding InformationFunding: R01HL12186106, R01HL136684‐02, R01HL136684, P01HL051971, P20GM104357, 5U54GM115428, T32HL105324, and 19POST34450074.