Development of a two-stage limb ischemia model to better simulate human peripheral artery disease

Autor: Jiaze Li, Smriti M. Krishna, Roby J. Jose, Jonathan Golledge, Safraz Mohamed Omer, Susan K. Morton
Jazyk: angličtina
Rok vydání: 2020
Předmět:
0301 basic medicine
Male
Vascular Endothelial Growth Factor A
Mice
Knockout
ApoE
lcsh:Medicine
Perfusion scanning
Femoral artery
Hindlimb
030204 cardiovascular system & hematology
Severity of Illness Index
chemistry.chemical_compound
Mice
0302 clinical medicine
Ischemia
Medicine
Treadmill
lcsh:Science
Multidisciplinary
3. Good health
Vascular endothelial growth factor
Femoral Artery
Experimental models of disease
Cardiology
Shear Strength
medicine.medical_specialty
Perfusion Imaging
TRPV Cation Channels
Article
03 medical and health sciences
Gastrocnemius muscle
Peripheral Arterial Disease
medicine.artery
Internal medicine
Physical Conditioning
Animal
Animals
Humans
Muscle
Skeletal
business.industry
lcsh:R
Blood flow
Translational research
medicine.disease
Fibrosis
Vascular Endothelial Growth Factor Receptor-2
Disease Models
Animal
030104 developmental biology
chemistry
lcsh:Q
business
Zdroj: Scientific Reports, Vol 10, Iss 1, Pp 1-16 (2020)
Scientific Reports
ISSN: 2045-2322
Popis: Peripheral arterial disease (PAD) develops due to the narrowing or blockage of arteries supplying blood to the lower limbs. Surgical and endovascular interventions are the main treatments for advanced PAD but alternative and adjunctive medical therapies are needed. Currently the main preclinical experimental model employed in PAD research is based on induction of acute hind limb ischemia (HLI) by a 1-stage procedure. Since there are concerns regarding the ability to translate findings from this animal model to patients, we aimed to develop a novel clinically relevant animal model of PAD. HLI was induced in male Apolipoprotein E (ApoE−/−) deficient mice by a 2-stage procedure of initial gradual femoral artery occlusion by ameroid constrictors for 14 days and subsequent excision of the femoral artery. This 2-stage HLI model was compared to the classical 1-stage HLI model and sham controls. Ischemia severity was assessed using Laser Doppler Perfusion Imaging (LDPI). Ambulatory ability was assessed using an open field test, a treadmill test and using established scoring scales. Molecular markers of angiogenesis and shear stress were assessed within gastrocnemius muscle tissue samples using quantitative polymerase chain reaction. HLI was more severe in mice receiving the 2-stage compared to the 1-stage ischemia induction procedure as assessed by LDPI (p = 0.014), and reflected in a higher ischemic score (p = 0.004) and lower average distance travelled on a treadmill test (p = 0.045). Mice undergoing the 2-stage HLI also had lower expression of angiogenesis markers (vascular endothelial growth factor, p = 0.004; vascular endothelial growth factor- receptor 2, p = 0.008) and shear stress response mechano-transducer transient receptor potential vanilloid 4 (p = 0.041) within gastrocnemius muscle samples, compared to animals having the 1-stage HLI procedure. Mice subjected to the 2-stage HLI receiving an exercise program showed significantly greater improvement in their ambulatory ability on a treadmill test than a sedentary control group. This study describes a novel model of HLI which leads to more severe and sustained ischemia than the conventionally used model. Exercise therapy, which has established efficacy in PAD patients, was also effective in this new model. This new model maybe useful in the evaluation of potential novel PAD therapies.
Databáze: OpenAIRE
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