LRRC8A-VRAC modulates the contractile response by managing the superoxide anion influx in diabetic vasculogenic erectile dysfunction

Abstract

Introduction: Erectile dysfunction (ED) may be an early marker for cardiovascular diseases, and it is often associated with an hypercontractility of the corpus cavernosum (CC) and pudendal artery (PA) because of increased reactive oxygen species (ROS). Leucine Rich Repeat Containing 8 (LRRC8) Volume Regulated Anion Channels (VRACs) regulates Nox1 and modulates the influx of extracellular superoxide anion (O2•-), contributing to the creation of an oxidized domain, enhancing calcium sensitivity of the smooth muscle which promotes contraction. Objective: We hypothesize that downregulation of NOX1 or LRRC8A would decrease the contractile responses to phenylephrine (PE) and electrical field stimulation (EFS) in the CC, PA and mesenteric resistance artery (MRA) of diabetic mice (dbdb−/−). Methods: The CC and PA of diabetic (dbdb−/−) mice were mounted in myographs. The contraction elicited by PE or EFS was performed in the presence of apocynin (non-selective NOX inhibitor) and GKT137831 (NOX1/4 inhibitor). In LRRC8A KO dbdb−/− mice, contractions to PE and EFS were obtained in the absence or in the presence of GKT137831.Results: In the CC, the maximal contraction to PE was increased in dbdb−/− animals, and in the presence of 3 mM of apocynin, the contractile response was markedly diminished in both control and dbdb−/−. Incubation with GKT137831 reduced the contraction elicited by PE only in the dbdb−/− group (68 ± 9% of the maximal contraction), whereas in the control group this reduction was not significant (82 ± 14% of the PE-maximal contraction). In the PA, the potency of PE was increased in the dbdb−/− group, and apocynin 1mM restored the contraction to normal levels. In the LRRC8A KO dbdb−/− mice, the contraction to PE in the MRA and PA was reduced by 30% compared to dbdb−/−. The response to EFS in CC was similar to dbdb−/−, however, GKT137831 reduced the contraction to EFS with lesser magnitude of inhibition in the LRRC8A KO dbdb−/− mice (35% of inhibition) compared to dbdb−/− mice (50% of inhibition), suggesting that the participation of O2•- in the contractile response was reduced by the lack of functional LRRC8A. Conclusion: LRRC8A modulates the contractile response by managing the influx of reactive oxygen species (ROS) in smooth muscle cells. Inhibition of LRRC8A may be a therapeutic target to prevent hypercontractility of arteries and CC in conditions where there are marked increases in ROS production, such as diabetes. NIH – R01 132948; Institute on Cardiovascular Disease Research, University of South Carolina. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.