Cysteinyl leukotriene receptor 2 (CysLT2R)‐mediated vascular permeability and ischemia/reperfusion injury

Abstract

Cysteinyl leukotrienes (CysLTs) are arachidonate‐derived lipid mediators of inflammation that act via CysLT receptors. Previously, we demonstrated that transgenic overexpression of the human CysLT2R in endothelium (hEC) exacerbates vascular permeability and inflammatory response activation. However, we could not delineate the relative contributions of endogenous mouse CysLT2R and the transgene‐derived receptor. Thus, we created a novel mouse strain (hECxKO) by crossing hEC mice with CysLT2R knockout mice in order to examine the specific roles of CysLT2R tissue‐localized expression niches in inflammation and tissue injury. Surprisingly, in contrast to our previous findings where myocardial ischemia/reperfusion injury was markedly enhanced in hEC mice compared to wildtype (WT) mice (47.3 ± 2.0% to 25.2 ± 3.5%), this was not the case with hECxKO mice, where injury was comparable to WT mice (24.0 ± 3.0%). Furthermore, in contrast to hEC and WT mice, hECxKO mice displayed altered leukotriene‐mediated vascular permeability responses, measured as FITC‐albumin leakage, in a cremaster muscle venule intravital imaging system. The data indicate that endothelial‐expressed CysLT2R mediates only part of the post‐injury inflammatory response to leukotrienes and that CysLT2R expressed in other uncharacterized sites is important. This work was supported by the CIHR and a Career Investigator award from the HSFO.