Impact of early life ovariectomy on blood pressure and body composition in a female mouse model of systemic lupus erythematosus

Abstract

Because of the preponderance of women affected by the chronic autoimmune disease systemic lupus erythematosus (SLE), estrogen is thought to contribute to SLE disease progression. This is supported by evidence from experimental animal models of SLE showing that removal of estrogen in young female mice delays autoantibody production and renal injury and lengthens survival. Blood pressure and changes in body composition are important cardiovascular risk factors that can be regulated by estrogens. Because cardiovascular disease is the leading cause of death in patients with SLE, we used an established female mouse model of SLE (NZBWF1) to test whether early life removal of estrogen impacts the development of hypertension and changes in body composition commonly associated with SLE. Eight-week-old female SLE and control mice (NZW/LacJ) underwent either a sham operation or ovariectomy. Body weight, body composition (fat and lean masses), and renal injury (albuminuria) were monitored until mice reached 34 wk of age, at which time mean arterial pressure was assessed in conscious animals by a carotid catheter. Early life removal of the ovaries delayed the onset of autoantibody production and albuminuria while causing an increase in body weight and fat mass. Blood pressure in the adult was not altered by early life removal of the ovaries. These data suggest that estrogens may have a permissive role for the development of SLE while helping to maintain normal body weight and composition, which is associated with reduced cardiovascular risk.

Connexin 43 hemichannels protect bone loss during estrogen deficiency

“…As reported previously, 27 at 4 weeks after surgery, the body weight of OVX mice was increased compared to sham-operated counterparts, along with a dramatically decreased size and weight of uterus (Fig. S2A).…”

Immunosuppression With Mycophenolate Mofetil Attenuates Hypertension in an Experimental Model of Autoimmune Disease

“…First, other established experimental models (ie, MRL/ lpr ) develop aggressive renal pathology that causes mortality typically by 20 weeks of age, but they do not develop hypertension . Second, studies from our laboratory show that albuminuria does not track with hypertension; for example, early life ovariectomy of NZBWF1 mice ameliorates albuminuria while hypertension persists . Importantly, this disconnect between nephritis and the development of hypertension during SLE has also been reported in humans …”

Understanding mechanisms of hypertension in systemic lupus erythematosus

“…This suggests that regulation of the RAS is largely intact in this model. Our laboratory has reported on several factors that contribute to hypertension in female NZBWF1 mice, including impaired renal hemodynamic function [Venegas-Pont et al 2011], vascular endothelial dysfunction [Ryan and McLemore, 2007], altered inflammatory cytokine profiles [Venegas-Pont et al 2010], oxidative stress [Mathis et al 2012], adaptive immune system dysfunction [Mathis et al 2014], and sex hormones [Gilbert et al 2014; Gilbert and Ryan, 2014]. …”

“…Consistent with these studies, our laboratory recently demonstrated that an early life ovariectomy (OVX) delayed the onset of albuminuria and autoantibody production and also caused an increase in body weight and fat mass. Early life OVX did not, however, alter blood pressure in adult NZBWF1 mice [Gilbert and Ryan, 2014]. Interestingly, the timing of estrogen removal (by OVX) appears to be important.…”