Oestrogen-mediated upregulation of the Mas receptor contributes to sex differences in acute lung injury and lung vascular barrier regulation

Abstract

Epidemiological data from the SARS-CoV-2 outbreak suggest sex differences in mortality and vulnerability; yet sex-dependent incidences of acute respiratory distress syndrome (ARDS) remain controversial and sex-dependent mechanisms of endothelial barrier regulation is unknown. In premenopausal women increased signalling of angiotensin (Ang)-(1–7) via the Mas receptor has been linked to lower cardiovascular risk. Since stimulation of the Ang-(1–7)/Mas axis protects the endothelial barrier in acute lung injury (ALI), we hypothesised that increased Ang-(1–7)/Mas signalling may protect females over males in ALI/ARDS. Clinical data were collected from Charité inpatients. Sex differences in ALI were assessed in wild-type (WT) and Mas-deficient (Mas^−/−) mice. Endothelial permeability was assessed as weight change in isolated lungs and as trans-endothelial electrical resistance in vitro. In 734 090 Charité inpatients (2005–2016), ARDS had a higher incidence in men as compared to women. In murine ALI, male WT mice had more lung edema, protein leak, and histological evidence of injury than female WT mice. Lung weight change in response to platelet-activating factor (PAF) was more pronounced in male WT and female Mas^−/− mice than female WT, whereas Mas receptor expression was higher in female WT lungs. Ovariectomy attenuated protection in female WT mice and reduced Mas receptor expression. In vitro, estrogen increased Mas receptor expression and attenuated endothelial leak in response to thrombin; this effect was alleviated by Mas receptor blockade. Improved lung endothelial barrier function protects female mice from ALI-induced lung edema. This effect is partially mediated via enhanced Ang-(1–7)/Mas signalling as a result of estrogen-dependent Mas expression.