Chronic liver scarring from any cause leads to cirrhosis, portal hypertension, and a progressive decline in renal blood flow and renal function. Extreme renal vasoconstriction characterizes hepatorenal syndrome, a functional and potentially reversible form of acute kidney injury in patients with advanced cirrhosis, but current therapy with systemic vasoconstrictors is ineffective in a substantial proportion of patients and is limited by ischemic adverse events. Serelaxin (recombinant human relaxin-2) is a peptide molecule with anti-fibrotic and vasoprotective properties that binds to relaxin family peptide receptor-1 (RXFP1) and has been shown to increase renal perfusion in healthy human volunteers. We hypothesized that serelaxin could ameliorate renal vasoconstriction and renal dysfunction in patients with cirrhosis and portal hypertension.

GPR81 (G-protein-coupled receptor 81) is highly expressed in adipocytes, and activation by the endogenous ligand lactate inhibits lipolysis. GPR81 is also expressed in the heart, liver, and kidney, but roles in nonadipose tissues are poorly defined. GPR81 agonists, developed to improve blood lipid profile, might also provide insights into GPR81 physiology. Here, we assessed the blood pressure and renal hemodynamic responses to the GPR81 agonist, AZ'5538. In male wild-type mice, intravenous AZ'5538 infusion caused a rapid and sustained increase in systolic and diastolic blood pressure. Renal artery blood flow, intrarenal tissue perfusion, and glomerular filtration rate were all significantly reduced. AZ'5538 had no effect on blood pressure or renal hemodynamics in Gpr81-/- mice. Gpr81 mRNA was expressed in renal artery vascular smooth muscle, in the afferent arteriole, in glomerular and medullary perivascular cells, and in pericyte-like cells isolated from kidney. Intravenous AZ'5538 increased plasma ET-1 (endothelin 1), and pretreatment with BQ123 (endothelin-A receptor antagonist) prevented the pressor effects of GPR81 activation, whereas BQ788 (endothelin-B receptor antagonist) did not. Renal ischemia-reperfusion injury, which increases renal extracellular lactate, increased the renal expression of genes encoding ET-1, KIM-1 (Kidney Injury Molecule 1), collagen type 1-α1, TNF-α (tumor necrosis factor-α), and F4/80 in wild-type mice but not in Gpr81-/- mice. In summary, activation of GPR81 in vascular smooth muscle and perivascular cells regulates renal hemodynamics, mediated by release of the potent vasoconstrictor ET-1. This suggests that lactate may be a paracrine regulator of renal blood flow, particularly relevant when extracellular lactate is high as occurs during ischemic renal disease.

Lymph nodes (LNs) are believed to be the first organs targeted by colorectal cancer cells detached from a primary solid tumor because of their role in draining interstitial fluids. Better detection and assessment of these organs have the potential to help clinicians in stratification and designing optimal design of oncological treatments for each patient. Whilst highly valuable for the detection of primary tumors, CT and MRI remain limited for the characterization of LNs. B-mode ultrasound (US) and contrast-enhanced ultrasound (CEUS) can improve the detection of LNs and could provide critical complementary information to MRI and CT scans; however, the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) guidelines advise that further evidence is required before US or CEUS can be recommended for clinical use. Moreover, knowledge of the lymphatic system and LNs is relatively limited, especially in preclinical models. In this pilot study, we have created a mouse model of metastatic cancer and utilized 3D high-frequency ultrasound to assess the volume, shape, and absence of hilum, along with CEUS to assess the flow dynamics of tumor-free and tumor-bearing LNs in vivo. The aforementioned parameters were used to create a scoring system to predict the likelihood of a disease-involved LN before establishing post-mortem diagnosis with histopathology. Preliminary results suggest that a sum score of parameters may provide a more accurate diagnosis than the LN size, the single parameter currently used to predict the involvement of an LN in disease.

Global deficiency of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), an enzyme that regenerates glucocorticoids within cells, promotes angiogenesis, and reduces acute infarct expansion after myocardial infarction (MI), suggesting that 11β-HSD1 activity has an adverse influence on wound healing in the heart after MI. The present study investigated whether 11β-HSD1 deficiency could prevent the development of heart failure after MI and examined whether 11β-HSD1 deficiency in cardiomyocytes and vascular smooth muscle cells confers this protection. Male mice with global deficiency in 11β-HSD1, or with Hsd11b1 disruption in cardiac and vascular smooth muscle (via SM22α-Cre recombinase), underwent coronary artery ligation for induction of MI. Acute injury was equivalent in all groups. However, by 8 weeks after induction of MI, relative to C57Bl/6 wild type, globally 11β-HSD1-deficient mice had reduced infarct size (34.7 ± 2.1% left ventricle [LV] vs 44.0 ± 3.3% LV, P = .02), improved function (ejection fraction, 33.5 ± 2.5% vs 24.7 ± 2.5%, P = .03) and reduced ventricular dilation (LV end-diastolic volume, 0.17 ± 0.01 vs 0.21 ± 0.01 mL, P = .01). This was accompanied by a reduction in hypertrophy, pulmonary edema, and in the expression of genes encoding atrial natriuretic peptide and β-myosin heavy chain. None of these outcomes, nor promotion of periinfarct angiogenesis during infarct repair, were recapitulated when 11β-HSD1 deficiency was restricted to cardiac and vascular smooth muscle. 11β-HSD1 expressed in cells other than cardiomyocytes or vascular smooth muscle limits angiogenesis and promotes infarct expansion with adverse ventricular remodeling after MI. Early pharmacological inhibition of 11β-HSD1 may offer a new therapeutic approach to prevent heart failure associated with ischemic heart disease.

Ultrasonic contrast agents are used routinely to aid clinical diagnosis. All premium- and mid-range scanners utilise contrast-specific imaging techniques to preferentially isolate and display the nonlinear signals generated from the microbubbles when insonated with a series of ultrasound pulses. In this manuscript the abilities of four premium ultrasound scanners to detect and display the ultrasound signal from two commercially available contrast agents-SonoVue and DEFINITY®-are compared. A flow phantom was built using tubes with internal diameters of 1.6 mm and 3.2 mm, suspended at depths of 1, 5 and 8 cm and embedded in tissue-mimicking material. Dilute solutions of SonoVue and DEFINITY® were pumped through the phantom at 0.25 mL/s and 1.5 mL/s. Four transducers were used to scan the tubes-a GE Logiq E9 (C2-9) curvilinear probe, a Philips iU22 L9-3 linear array probe, an Esaote MyLab Twice linear array LA523 (4-13 MHz) and a Fujifilm VisualSonics Vevo3100 MX250 (15-30 MHz) linear array probe. We defined a new parameter to compare the ability of the ultrasound scanners to display the contrast enhancement. This was defined as the ratio of grey-scale intensity ratio in contrast-specific imaging mode relative to the B-mode intensity from the same region-of-interest within the corresponding B-mode image. The study demonstrated that the flow rates used in this study had no effect on the contrast-specific imaging mode to B-mode (CSIM-BM) ratio for the three clinical scanners studied, with SonoVue demonstrating broadly similar CSIM-BM ratios across all 3 clinical scanners. DEFINITY® also displayed similar results to SonoVue except when insonated with the Esaote MyLab Twice LA523 transducer, where it demonstrated significantly higher CSIM-BM ratios at superficial depths.

To support acquisition of accurate, reproducible and high-quality preclinical imaging data, various standardisation resources have been developed over the years. However, it is unclear the impact of those efforts in current preclinical imaging practices. To better understand the status quo in the field of preclinical imaging standardisation, the STANDARD group of the European Society of Molecular Imaging (ESMI) put together a community survey and a forum for discussion at the European Molecular Imaging Meeting (EMIM) 2022. This paper reports on the results from the STANDARD survey and the forum discussions that took place at EMIM2022.

The small size and high heart rate of the neonatal mouse heart makes structural and functional characterisation particularly challenging. Here, we describe application of electrocardiogram-gated kilohertz visualisation (EKV) ultrasound imaging with high spatio-temporal resolution to non-invasively characterise the post-natal mouse heart during normal growth and regeneration after injury. The 2-D images of the left ventricle (LV) acquired across the cardiac cycle from post-natal day 1 (P1) to P42 revealed significant changes in LV mass from P8 that coincided with a switch from hyperplastic to hypertrophic growth and correlated with ex vivo LV weight. Remodelling of the LV was indicated between P8 and P21 when LV mass and cardiomyocyte size increased with no accompanying change in LV wall thickness. Whereas Doppler imaging showed the expected switch from LV filling driven by atrial contraction to filling by LV relaxation during post-natal week 1, systolic function was retained at the same level from P1 to P42. EKV ultrasound imaging also revealed loss of systolic function after induction of myocardial infarction at P1 and regain of function associated with regeneration of the myocardium by P21. EKV ultrasound imaging thus offers a rapid and convenient method for routine non-invasive characterisation of the neonatal mouse heart.

Mouse models are used to study mechanisms that link intrauterine infection and preterm birth (PTB). To mimic intrauterine infection, lipopolysaccharide (LPS) is commonly injected into the uterus via minilaparotomy, which is invasive, and can cause PTB in control animals. We hypothesized that less-invasive ultrasound-guided intrauterine LPS injection or intravaginal LPS administration could induce PTB by stimulating an inflammatory response of the uteroplacental tissues, while minimizing PTB in control animals. On day 17 of gestation mice received LPS intravaginally (10 to 240 μg; n = 3 to 8) or into the uterus (20 μg) under ultrasound guidance (n = 7) or via laparotomy (n = 7). Control animals received phosphate-buffered saline (PBS; n = 5 to 7). Intrauterine administration of LPS, both under ultrasound guidance and via laparotomy, induced delivery earlier than in PBS control groups (P < 0.01). Intravaginal LPS administration did not stimulate PTB. Quantitative real-time PCR and immunohistochemistry of tissues harvested 6 hours after treatment confirmed that ultrasound-guided LPS administration induced a localized inflammatory response. Ultrasound-guided intrauterine LPS injection reliably induces PTB in the mouse and mimics the local inflammatory and immune responses observed in the more-invasive laparotomy model of inflammation-induced PTB. Ultrasound-guided intrauterine LPS injection is a useful novel model of PTB for future studies and concords with the principles of reduction, replacement, and refinement.

Corticosteroids directly affect the heart and vasculature and are implicated in the pathogenesis of heart failure. Attention is focussed upon the role of the mineralocorticoid receptor (MR) in mediating pro-fibrotic and other adverse effects of corticosteroids upon the heart. In contrast, the role of the glucocorticoid receptor (GR) in the heart and vasculature is less well understood. We addressed this in mice with cardiomyocyte and vascular smooth muscle deletion of GR (SMGRKO mice). Survival of SMGRKO mice to weaning was reduced compared with that of littermate controls. Doppler measurements of blood flow across the mitral valve showed an elongated isovolumetric contraction time in surviving adult SMGRKO mice, indicating impairment of the initial left ventricular contractile phase. Although heart weight was elevated in both genders, only male SMGRKO mice showed evidence of pathological cardiomyocyte hypertrophy, associated with increased myosin heavy chain-β expression. Left ventricular fibrosis, evident in both genders, was associated with elevated levels of mRNA encoding MR as well as proteins involved in cardiac remodelling and fibrosis. However, MR antagonism with spironolactone from birth only modestly attenuated the increase in pro-fibrotic gene expression in SMGRKO mice, suggesting that elevated MR signalling is not the primary driver of cardiac fibrosis in SMGRKO mice, and cardiac fibrosis can be dissociated from MR activation. Thus, GR contributes to systolic function and restrains normal cardiac growth, the latter through gender-specific mechanisms. Our findings suggest the GR:MR balance is critical in corticosteroid signalling in specific cardiac cell types.