Female Rats Artificially Selected for Low and High Intrinsic Aerobic Capacity Swap Inflammatory Cascade in Resistance Arteries: Mechanisms of Cyclooxygenase‐Derived Prostanoids

Abstract

Low‐capacity runner (LCR) rats and high‐capacity runner (HCR) rats are translational models of human physiology as they present a genetic predisposition towards disease and the ultra‐healthy state, respectively. Selected for their low (LCR) and high (HCR) intrinsic aerobic capacity, LCR rats display increased risk of metabolic syndrome and vascular inflammation, whereas HCR rats have decreased risk factors. Cyclooxygenase (COX) is an enzyme that plays a key role in inflammation as well as normal vascular physiology; however, it is unknown if rats with low or high intrinsic capacity present differences in the COX‐induced inflammatory cascade. As obese females display an increased risk to cardiovascular disease compared to males, female LCR rats were used as a model for metabolic syndrome. Therefore, we hypothesized that resistance arteries from female LCR rats would show increased COX activity, while arteries from female HCR rats would show decreased COX activity.Our rat model (female, 18–25 weeks old) study used LCR, HCR, and high‐response trained (HRT) rats as control (n=4/group). HRT rats have a trained aerobic capacity that is higher than LCR but lower than HCR. We quantified cardiac hypertrophy by dividing the left ventricle weight by 26.73 + tibia length (TL)3. Statistics: t‐test: p<0.05: * vs control (HRT); # vs. HCR; & vs. absence of indomethacin (Indo). No differences in fat pad weight between HRT and HCR were observed. However, LCR rats showed increased fat pad weight when compared to HCR [HRT: 1.05±0.2 vs. LCR: 1.57±0.2#; HCR: 0.92±0.1 (g)]. As expected, HCR presented an increased left ventricle weight, indicating physiologic hypertrophy, when compared to LCR. No differences were observed between LCR and control [HRT: 6.84±0.9 vs. LCR: 6.55±0.1#; HCR: 7.73±0.3; 26.73+TL3]. Mesenteric resistance arteries (MRA) were extracted and mounted onto a wire myograph. No significant differences were observed in the acetylcholine and phenylephrine (PE) concentration‐response curves between groups. As expected, arteries from HRT and LCR rats incubated with a nonspecific COX inhibitor [indomethacin (Indo), 10 μM] presented a significant decrease in contraction. Interestingly, indomethacin did not alter or decrease phenylephrine‐induced contraction in arteries from HCR [PE: Emax%: HRT: control 93±3 vs. Indo 3±0.6&; LCR: control 62±17 vs. Indo 2±0.7&; HCR: control 94±6 vs. Indo 80±9] (Fig 1). Overall, these data reveal a new, dichotomous mechanism for vascular inflammation and contractility in LCR and HCR rats. Specifically, we observed that arteries from female rats born with high aerobic capacity are unresponsive to COX inhibition during phenylephrine contraction, perhaps to maintain the high vascular flow needed for their higher exercise metabolism. This may be caused by a swap mechanism from a normal inflammatory state to a higher inflammatory‐resolution state. Our study constitutes the basis for the discovery of new therapeutic targets for vascular inflammation in people with high aerobic capacity.Support or Funding InformationThis work was supported by National Institutes of Health (NIH) (NIH: R00GM118885)Concentration‐response curves to phenylephrine, with and without indomethacin (10 uM), in mesenteric resistance arteries (MRA) from (A) HRT, (B) LCR, and (C) HCR rats. (D) The average maximum response (Emax) of MRA to phenylephrine, with and without indomethacin (10 uM). T‐test: & vs. absence of Indo p<0.05.Figure 1