New approaches in small animal echocardiography: imaging the sounds of silence

Systolic and diastolic dysfunction of the left ventricle (LV) is a hallmark of most cardiac diseases. In vivo assessment of heart function in animal models, particularly mice, is essential to refining our understanding of cardiovascular disease processes. Ultrasound echocardiography has emerged as a powerful, noninvasive tool to serially monitor cardiac performance and map the progression of heart dysfunction in murine injury models. This review covers current applications of small animal echocardiography, as well as emerging technologies that improve evaluation of LV function. In particular, we describe speckle-tracking imaging-based regional LV analysis, a recent advancement in murine echocardiography with proven clinical utility. This sensitive measure enables an early detection of subtle myocardial defects before global dysfunction in genetically engineered and rodent surgical injury models. Novel visualization technologies that allow in-depth phenotypic assessment of small animal models, including perfusion imaging and fetal echocardiography, are also discussed. As imaging capabilities continue to improve, murine echocardiography will remain a critical component of the investigator's armamentarium in translating animal data to enhanced clinical treatment of cardiovascular diseases.

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Animal Models of Colorectal Cancer: From Spontaneous to Genetically Engineered Models and Their Applications

Veterinary Sciences ◽

10.3390/vetsci8040059 ◽

2021 ◽

Vol 8 (4) ◽

pp. 59

Author(s):

Elisabete Nascimento-Gonçalves ◽

Bruno A.L. Mendes ◽

Rita Silva-Reis ◽

Ana I. Faustino-Rocha ◽

Adelina Gama ◽

...

Keyword(s):

Colorectal Cancer ◽

Animal Models ◽

Cancer Progression ◽

Social Impact ◽

Genetically Engineered ◽

In Vivo Studies ◽

Gastrointestinal Malignancies ◽

Advantages And Disadvantages ◽

Colon Cancer Progression

Colorectal cancer is one of the most common gastrointestinal malignancies in humans, affecting approximately 1.8 million people worldwide. This disease has a major social impact and high treatment costs. Animal models allow us to understand and follow the colon cancer progression; thus, in vivo studies are essential to improve and discover new ways of prevention and treatment. Dietary natural products have been under investigation for better and natural prevention, envisioning to show their potential. This manuscript intends to provide the readers a review of rodent colorectal cancer models available in the literature, highlighting their advantages and disadvantages, as well as their potential in the evaluation of several drugs and natural compounds’ effects on colorectal cancer.

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Abstract 228: Alterations of Cardiac Morphology and Function Caused by Cardio-Thoracic Surgery in Small Animal Models of Heart Disease

Circulation Research ◽

10.1161/res.113.suppl_1.a228 ◽

2013 ◽

Vol 113 (suppl_1) ◽

Author(s):

Peter Nordbeck ◽

Leoni Bönhof ◽

Karl-Heinz Hiller ◽

Sabine Voll ◽

Paula Arias ◽

...

Keyword(s):

Body Weight ◽

Heart Disease ◽

Animal Models ◽

Right Ventricular ◽

Small Animal ◽

Cardiac Morphology ◽

Small Animal Models ◽

And Function

Background: Surgical procedures in small animal models of heart disease, such as artificial ligation of the coronary arteries for experimental myocardial infarction, can evoke alterations in cardiac morphology and function. Such alterations might induce artificial early or long term effects in vivo that might account for a significant bias in basic cardiovascular research, and, therefore, could potentially question the meaning of respective studies in small animal models of heart disease. Methods: Female Wistar rats were matched for weight and distributed to sham left coronary artery ligation or untreated control. Cardiac parameters were then investigated in vivo by high-field MRI over time after the surgical procedure, determining left and right ventricular morphology and function. Additionally, the time course of several metabolic and inflammatory blood parameters was determined. Results: Rats after sham surgery showed a lower body weight for up to 8 weeks after the intervention compared to healthy controls. Left and right ventricular morphology and function were not different in absolute measures in both groups 1 week after surgery. However, there was a confined difference in several cardiac parameters normalized to the body weight (bw), such as myocardial mass (2.19±0.30/0.83±0.13 vs. 1.85±0.22/0.70±0.07 mg left/right per g bw, p<0.05), or enddiastolic ventricular volume (1.31±0.36/1.21±0.31 vs. 1.14±0.20/1.07±0.17 µl left/right per g bw, p<0.05). Vice versa, after 8 weeks, cardiac masses, volumes, and output showed a trend for lower values in the sham operated rats compared to the controls in absolute measures (782.2±57.2/260.2±33.2 vs. 805.9±84.8/310.4±48.5 mg, p<0.05 for left/right ventricular mass), but not normalized to body weight. Matching these findings, blood testing revealed prolonged metabolic and inflammatory changes after surgery not related to cardiac disease. Conclusion: There is a small distinct impact of cardio-thoracic surgical procedures on the global integrity of the organism, which in the long term also includes circumscribed repercussions on cardiac morphology and function. This impact has to be considered when analyzing data from respective studies and transferring the findings to conditions in patients.

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Neuromuscular Development and Disease: Learning From in vitro and in vivo Models

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.764732 ◽

2021 ◽

Vol 9 ◽

Author(s):

Zachary Fralish ◽

Ethan M. Lotz ◽

Taylor Chavez ◽

Alastair Khodabukus ◽

Nenad Bursac

Keyword(s):

Skeletal Muscle ◽

Cell Culture ◽

Animal Models ◽

Schwann Cells ◽

Motor Neurons ◽

Small Animal ◽

In Vivo Models ◽

Small Animal Models

The neuromuscular junction (NMJ) is a specialized cholinergic synaptic interface between a motor neuron and a skeletal muscle fiber that translates presynaptic electrical impulses into motor function. NMJ formation and maintenance require tightly regulated signaling and cellular communication among motor neurons, myogenic cells, and Schwann cells. Neuromuscular diseases (NMDs) can result in loss of NMJ function and motor input leading to paralysis or even death. Although small animal models have been instrumental in advancing our understanding of the NMJ structure and function, the complexities of studying this multi-tissue system in vivo and poor clinical outcomes of candidate therapies developed in small animal models has driven the need for in vitro models of functional human NMJ to complement animal studies. In this review, we discuss prevailing models of NMDs and highlight the current progress and ongoing challenges in developing human iPSC-derived (hiPSC) 3D cell culture models of functional NMJs. We first review in vivo development of motor neurons, skeletal muscle, Schwann cells, and the NMJ alongside current methods for directing the differentiation of relevant cell types from hiPSCs. We further compare the efficacy of modeling NMDs in animals and human cell culture systems in the context of five NMDs: amyotrophic lateral sclerosis, myasthenia gravis, Duchenne muscular dystrophy, myotonic dystrophy, and Pompe disease. Finally, we discuss further work necessary for hiPSC-derived NMJ models to function as effective personalized NMD platforms.

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Magnetic Resonance Imaging in Animal Models of Alzheimer’s Disease Amyloidosis

10.20944/preprints202110.0231.v1 ◽

2021 ◽

Author(s):

Ruiqing Ni

Keyword(s):

Magnetic Resonance Imaging ◽

Magnetic Resonance ◽

Animal Models ◽

Amyloid Beta ◽

High Field ◽

Diffusion Tensor ◽

Small Animal ◽

Resonance Imaging ◽

Magnetic Resonance Imaging Mri

Amyloid-beta plays an important role in the pathogenesis of Alzheimer’s disease. Aberrant amyloid-beta and tau accumulation induce neuroinflammation, cerebrovascular alterations, synaptic deficits, functional deficits, and neurodegeneration, leading to cognitive impairment. Animal models recapitulating the amyloid-beta pathology such as transgenic, knock-in mouse and rat models have facilitated the understanding of disease mechanisms and development of therapeutics targeting at amyloid-beta. There is a rapid advance in high-field MR in small animals. Versatile high-field magnetic resonance imaging (MRI) sequences such as diffusion tensor imaging, arterial spin labelling, resting-state functional MRI, anatomical MRI, MR spectroscopy as well as contrast agents have been developed for the applications in animal models. These tools have enabled high-resolution in vivo structural, functional, and molecular readouts with a whole brain field-of-view. MRI have been utilized to visualize non-invasively the amyloid-beta deposits, synaptic deficits, regional brain atrophy, impairment in white matter integrity, functional connectivity, cerebrovascular and glymphatic system in animal models of amyloidosis. Many of the readouts are translational in clinical MRI in the brain of patients with Alzheimer’s disease. In this review, we summarize the recent advance of using MRI for visualizing the pathophysiology in amyloidosis animal model. We discuss the outstanding challenges in brain imaging using MRI in small animal and propose future outlook in visualizing amyloid-beta-related alterations in brain of animal models.

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Impact of exercise training on ventricular properties in a canine model of congestive heart failure

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1997.272.3.h1382 ◽

1997 ◽

Vol 272 (3) ◽

pp. H1382-H1390 ◽

Cited By ~ 4

Author(s):

K. Todaka ◽

J. Wang ◽

G. H. Yi ◽

M. Knecht ◽

R. Stennett ◽

...

Keyword(s):

Heart Failure ◽

Exercise Training ◽

Heart Function ◽

Systolic Pressure ◽

Cardiac Pacing ◽

Left Ventricular ◽

Lv Function ◽

Myocardial Stiffness

Exercise training improves functional class in patients with chronic heart failure (CHF) via effects on the periphery with no previously documented effect on intrinsic left ventricular (LV) properties. However, because methods used to evaluate in vivo LV function are limited, it is possible that some effects of exercise training on the failing heart have thus far eluded detection. Twelve dogs were instrumented for cardiac pacing and hemodynamic recordings. Hearts were paced rapidly for 4 wk. Six of the dogs received daily treadmill exercise (CHF(EX), 4.4 km/h, 2 h/day) concurrent with rapid pacing, while the other dogs remained sedentary (CHFs). Hemodynamic measurements taken in vivo at the end of 4 wk revealed relative preservation of maximum rate of pressure rise (2,540 +/- 440 vs. 1,720 +/- 300 mmHg/s, P < 0.05) and LV end-diastolic pressure (9 +/- 5 vs. 19 +/- 4 mmHg, P < 0.05) in CHF(EX) compared with CHFs. The hearts were then isolated and cross perfused for in vitro measurement of isovolumic pressure-volume relations; these results were compared with those of six normal dogs (N). Systolic function was similarly depressed in both groups of pacing animals [end-systolic elastance (Ees) values of 1.66 +/- 0.47 in CHFs, 1.77 +/- 0.38 in CHF(EX), and 3.05 +/- 0.81 mmHg/ml in N, with no changes in volume axis interceptors of the end-systolic pressure-volume relationship]. The diastolic myocardial stiffness constant, k, was elevated in CHFs and was normalized by exercise training (32 +/- 3 in CHFs, 21 +/- 3 in CHF(EX), 20 +/- 4 in N). Thus daily exercise training preserved in vivo hemodynamics during 4 wk of rapid cardiac pacing and was accompanied by a significant change in diastolic myocardial stiffness in vitro. These findings suggest that changes in heart function may contribute to the overall beneficial hemodynamic effects of exercise training in CHF by a significant effect on diastolic properties.

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Sphingolipids as a Novel Therapeutic Target in Radiation-Induced Lung Injury

Cell Biochemistry and Biophysics ◽

10.1007/s12013-021-01022-8 ◽

2021 ◽

Author(s):

Jeffrey R. Jacobson

Keyword(s):

Lung Injury ◽

Cell Injury ◽

Inflammatory Responses ◽

Small Animal ◽

Protective Effects ◽

Sphingosine 1 Phosphate ◽

Radiation Induced ◽

Injury Models

AbstractRadiation-induced lung injury (RILI) is a potential complication of thoracic radiotherapy that can result in pneumonitis or pulmonary fibrosis and is associated with significant morbidity and mortality. The pathobiology of RILI is complex and includes the generation of free radicals and DNA damage that precipitate oxidative stress, endothelial cell (EC), and epithelial cell injury and inflammation. While the cellular events involved continue to be elucidated and characterized, targeted and effective therapies for RILI remain elusive. Sphingolipids are known to mediate EC function including many of the cell signaling events associated with the elaboration of RILI. Sphingosine-1-phosphate (S1P) and S1P analogs enhance EC barrier function in vitro and have demonstrated significant protective effects in vivo in a variety of acute lung injury models including RILI. Similarly, statin drugs that have pleiotropic effects that include upregulation of EC S1P receptor 1 (S1PR1) have been found to be strongly protective in a small animal RILI model. Thus, targeting of EC sphingosine signaling, either directly or indirectly, to augment EC function and thereby attenuate EC permeability and inflammatory responses, represents a novel and promising therapeutic strategy for the prevention or treatment of RILI.

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A short term treatment with a Mek1/2 inhibitor promotes myocardial arteriogenesis and perfusion in vivo: focus on cardiac mural cells

European Heart Journal ◽

10.1093/ehjci/ehaa946.3779 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

E Avolio ◽

A Thomas ◽

A Caporali ◽

M Meloni ◽

M Caputo ◽

...

Keyword(s):

Molecular Mechanisms ◽

Culture Media ◽

Heart Function ◽

Lv Function ◽

Funding Source ◽

Short Term Treatment ◽

Short Treatment ◽

Mural Cells ◽

Vascular Regeneration

Abstract Background Arteriogenesis is crucial for heart recovery after ischaemia, but cellular and molecular mechanisms able to foster this phenomenon are still poorly characterised. Purpose To discover novel pro-arteriogenic approaches by exploiting cardiac mural cells endowed with arteriogenic capacity: pericytes (PCs) and vascular smooth muscle cells (VSMCs). Methods and results We derived human and murine CD31neg CD34pos cardiac PCs (cPCs) from myocardial samples of adult subjects and confirmed the pericyte phenotype and function in vitro. We discovered that the withdrawal of EGF and bFGF from the culture media induces the differentiation of cPCs into contractile VSMCs. Molecular investigations of pathways associated with the two factors showed that the Mek1/2-Erk1/2 signalling exerts an inhibitory transcriptional control on contractile VSMC genes. Screening of compounds able to interfere with this pathway revealed that PD0325901 – a potent Mek1/2 inhibitor (MeKi) tested in clinical trials for the treatment of cancer – activates the VSMC phenotype in cPCs. We observed a similar effect on coronary artery VSMCs. Next, we interrogated the effect of PD0325901 on cardiac arteriogenesis in vivo. Adult C57BL6/J mice were given the MeKi 10 mg/kg/day or vehicle (DMSO), orally for 14 days (n=11/group). At the endpoint, echocardiographic evaluation of left ventricle (LV) function and dimensions (n=6/group) showed no difference in comparison with the respective baseline in both groups. Effective inhibition of Mek1/2 in the heart of PD-treated mice was confirmed by the reduced immunostaining for the phosphorylated form of Erk1/2. The MeKi cardiotoxicity was ruled out by assessment of cardiomyocytes and vascular cells apoptosis (Tunel) and plasmatic levels of cTn-I. Histological analyses of the hearts (n=5/group) showed an increase in small arterioles (diameter <20μm) density in the LV of PD-mice compared with the DMSO group (16.4 vs 11.7 art/mm2). No change was observed for the capillary density. The drug promoted the maturation of VSMCs within both small and large (>20μm) arterioles, as shown by the higher ratio between the areas of the vascular wall occupied by the mature contractile marker SM myosin heavy chain and the synthetic/early contractile marker alpha-SM actin (αSMA). The PD treatment reduced the fraction of small arterioles covered with a CD34pos layer (53% vs 70% of total arterioles), along with a lower ratio between the areas occupied by adventitial CD34pos cells and αSMApos VSMCs, suggesting a contribution of cPCs to the arteriolar remodelling. Last, the drug improved the LV myocardial perfusion in the PD- vs the DMSO-group (6.8 vs 5.3 ml/min/g of LV tissue, n=6/group). Conclusions We show that a short treatment with a Mek1/2 inhibitor stimulates myocardial arteriogenesis and perfusion without either inducing cardiotoxicity or deteriorating heart function. This may be a novel, intriguing approach to promote therapeutic arteriogenesis. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): British Heart Foundation Centre for Vascular Regeneration II

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