Relaxin is a potent vasodilator of small resistance arteries and modifies arterial compliance in some systemic vascular beds, yet receptors for relaxin, such as RXFP1, have only been localized to vascular smooth muscle. This study first aimed to localize RXFP1 in rat arteries and veins from different organ beds and determine whether receptors are present in endothelial cells. We then tested the hypothesis that region‐specific vascular effects of relaxin may be influenced by the cellular localization of RXFP1 within different blood vessels. The aorta, vena cava, mesenteric artery, and vein had significantly higher ( P <0.05) RXFP1 immunostaining in endothelial cells compared with vascular smooth muscle, whereas the femoral artery and vein and small pulmonary arteries had higher ( P <0.01) RXFP1 immunostaining in the vascular smooth muscle. Male rats were treated subcutaneously with recombinant human relaxin‐2 (serelaxin; 4 μg/h) for 5 d; vasodilation and compliance in mesenteric and femoral arteries and veins were compared with placebo controls. Serelaxin significantly ( P =0.04) reduced wall stiffness and increased volume compliance in mesenteric arteries but not in the other vessels examined. This was associated with changes in geometrical properties, and not compositional changes in the extracellular matrix. Serelaxin treatment had no effect on acetylcholine‐mediated relaxation but significantly ( P < 0.001) enhanced bradykinin (BK)‐mediated relaxation in mesenteric arteries, involving enhanced nitric oxide but not endothelium‐derived hyperpolarization or vasodilatory prostanoids. In conclusion, there is differential distribution of RXFP1 on endothelial and smooth muscle across the vasculature. In rats, mesenteric arteries exhibit the greatest functional response to chronic serelaxin treatment.—Jelinic, M., Leo, C‐H., Post Uiterweer, E. P., Sandow, S. L., Gooi, J. H., Wlodek, M. E., Conrad, K. P., Parkington, H., Tare, M., Parry, L. J. Localization of relaxin receptors in arteries and veins, and region‐specific increases in compliance and bradykinin‐mediated relaxation after in vivo serelaxin treatment. FASEB J . 28, 275–287 (2014). www.fasebj.org

Obesity is defined as the excessive accumulation of body fat and is associated with an increased risk of developing major health problems such as cardiovascular disease, diabetes and stroke. There are clear sexual dimorphisms in the epidemiology, pathophysiology and sequelae of obesity and its accompanying metabolic disorders, with females often better protected compared to males. This protection has predominantly been attributed to the female sex hormone estrogen and differences in fat distribution. More recently, the sexual dimorphisms of obesity have also been attributed to the differences in the composition and function of the gut microbiota, and the intestinal immune system. This review will comprehensively summarize the pre-clinical and clinical evidence for these sexual dimorphisms and discuss the interplay between sex hormones, intestinal inflammation and the gut microbiome in obesity. Major gaps and limitations of this rapidly growing area of research will also be highlighted in this review.

Preeclampsia affects up to 8% of pregnancies worldwide and is a leading cause of both maternal and fetal morbidity and mortality. Our current understanding of the cause(s) of preeclampsia is far from complete, and the lack of a single reliable animal model that recapitulates all aspects of the disease further confounds our understanding. This is partially due to the heterogeneous nature of the disease, coupled with our evolving understanding of its etiology. Nevertheless, animal models are still highly relevant and useful tools that help us better understand the pathophysiology of specific aspects of preeclampsia. This review summarizes the various types and characteristics of animal models used to study preeclampsia, highlighting particular features of these models relevant to clinical translation. This review points out the strengths and limitations of these models to illustrate the importance of using the appropriate model depending on the research question.

IL-18 (interleukin-18) is elevated in hypertensive patients, but its contribution to high blood pressure and end-organ damage is unknown. We examined the role of IL-18 in the development of renal inflammation and injury in a mouse model of low-renin hypertension. Hypertension was induced in male C57BL6/J (WT) and IL-18 ^−/− mice by uninephrectomy, deoxycorticosterone acetate (2.4 mg/d, s.c.) and 0.9% drinking saline (1K/DOCA/salt). Normotensive controls received uninephrectomy and placebo (1K/placebo). Blood pressure was measured via tail cuff or radiotelemetry. After 21 days, kidneys were harvested for (immuno)histochemical, quantitative-PCR and flow cytometric analyses of fibrosis, inflammation, and immune cell infiltration. 1K/DOCA/salt-treated WT mice developed hypertension, renal fibrosis, upregulation of proinflammatory genes, and accumulation of CD3 ⁺ T cells in the kidneys. They also displayed increased expression of IL-18 on tubular epithelial cells. IL-18 ^−/− mice were profoundly protected from hypertension, renal fibrosis, and inflammation. Bone marrow transplantation between WT and IL-18 ^−/− mice revealed that IL-18-deficiency in non-bone marrow-derived cells alone afforded equivalent protection against hypertension and renal injury as global IL-18 deficiency. IL-18 receptor subunits—interleukin-18 receptor 1 and IL-18R accessory protein—were upregulated in kidneys of 1K/DOCA/salt-treated WT mice and localized to T cells and tubular epithelial cells. T cells from kidneys of 1K/DOCA/salt-treated mice produced interferon-γ upon ex vivo stimulation with IL-18, whereas those from 1K/placebo mice did not. In conclusion, IL-18 production by tubular epithelial cells contributes to elevated blood pressure, renal inflammation, and fibrosis in 1K/DOCA/salt-treated mice, highlighting it as a promising therapeutic target for hypertension and kidney disease.

Background: A recent clinical trial ( RELAX in in Acute Heart Failure [ RELAX ‐ AHF ]) demonstrated that 48 hours of continuous intravenous infusion of the vasorelaxant peptide serelaxin (recombinant human relaxin‐2) to patients with acute heart failure reduced cardiovascular mortality at 180 days. The persistence of a vasorelaxant response as a potential mechanism for this long‐term benefit and the vascular effects of a bolus intravenous injection of serelaxin have not been examined. This study investigates changes in resistance artery reactivity and passive mechanical wall properties following an intravenous serelaxin injection and whether these vascular effects persist in the absence of detectable circulating serelaxin. Methods and Results: Male rats were injected with 13.3 μg/kg serelaxin into the tail vein; mesenteric arteries were assessed 3 and 24 hours after treatment by using wire‐myography. Serelaxin increased basal nitric oxide synthase activity and reduced maximal contraction to endothelin‐1 at 3 hours after administration. Serelaxin treatment also selectively enhanced bradykinin‐mediated endothelium‐dependent relaxation. This effect was sustained for 24 hours in the absence of circulating serelaxin. Serelaxin‐mediated augmentation of bradykinin‐evoked relaxation involved endothelium‐derived hyperpolarization after 3 hours and prostacyclin‐mediated relaxation after 24 hours. Furthermore, upregulation of inducible nitric oxide synthase, phosphorylation of protein kinase B at Ser473 and endothelial nitric oxide synthase at Ser1177 was observed at 24 hours after serelaxin injection. There were no effects of serelaxin on passive arterial wall stiffness. Conclusion: Our data show that a bolus intravenous injection of serelaxin modulates endothelial vasodilator function 3 hours after administration, an effect that was sustained for 24 hours. The prolonged bradykinin‐mediated vasorelaxation is principally mediated through prostacyclin.