Sigmar1 Deficiency Promotes Inflammatory Signals By Altering Nitric Oxide Bioavailability And Mitochondrial Redox Balance In Vascular Endothelial Cells

Mitochondria in endothelial cells primarily serve as major signaling organelles thatregulate cellular redox balance and associated nitric oxide (NO) bioavailability.Mitochondrial reactive oxygen species (ROS) and NO have pro- and anti-inflammatoryeffects, respectively. Imbalance of these molecules leads to endothelial activation andvascular inflammation initiating the development of major cardiovascular diseases.Sigma1 receptor (Sigmar1) protein is a mitochondrial membrane protein regulatingmitochondrial respiration and function. Only few previous studies have identifiedSigmar1’s roles in vascular function and inflammation using nonselective ligands inpreclinical pathological models. However, the direct physiological role and molecularmechanisms of Sigmar1 in regulating vascular endothelial function and inflammationremains unknown. In this study, we have confirmed Sigmar1’s expression in vascularendothelial cells and analyzed its function in vascular inflammation using cell cultureand mice models. In flow mediated dilation study of left femoral artery, our globalSigmar1 knockout (Sigmar1 -/- ) mice failed to increase the vessel diameter and bloodflow velocity in response to reactive hyperemia compared to wild type littermate control(Wt) mice (N=6/group). We also found reduced nitric oxide (NO) bioavailability in theplasma of Sigmar1 -/- mice. Consistently, phosphorylated-eNOS (ser-1177) expressionwas significantly decreased in Sigmar1 -/- mice aorta and in mouse pulmonarymicrovascular ECs (MPVECs) isolated from Sigmar1 -/- mice. Ultrastructural analysis ofthe Sigmar1 -/- mice aorta showed altered mitochondrial morphology with elongatedshaped mitochondria and reduced mitochondrial respiration. The MPVECs isolated fromSigmar1 -/- mice also showed decreased mitochondrial respiration, higher proteinexpression of mitochondrial superoxide dismutase and catalase. Finally, we observedelevation of inflammatory markers including VCAM1 and ICAM1 in Sigmar1 deficientMPVECs and higher vascular remodeling indicated by increased fibrosis in blood thevessels of Sigmar1 -/- mice. Overall, Sigmar1 regulates endothelial inflammation byaltering mitochondrial redox balance and NO bioavailability.