The Challenge of Cardiovascular Disease Modeling
Cardiovascular diseases encompass a diverse range of conditions affecting the heart and blood vessels. Mouse models must capture relevant aspects of human disease while accounting for important species differences in cardiovascular physiology and lipid metabolism.
Species Considerations
Mice differ from humans in several cardiovascular relevant ways:
Lipid Metabolism
Mice carry most cholesterol in HDL rather than LDL, making them naturally resistant to atherosclerosis. Genetic modifications disrupting ApoE or LDLR function are typically required to create hypercholesterolemia and vascular disease.
Heart Rate and Size
Mouse hearts beat approximately 600 times per minute compared to 60 to 100 in humans. Cardiac remodeling processes may differ due to these physiological differences.
Coronary Anatomy
Mouse coronary arteries are small and follow different branching patterns than human coronaries. Spontaneous coronary atherosclerosis is rare even in hyperlipidemic models.
Choosing the Right Model System
Different cardiovascular questions require different modeling approaches:
Atherosclerosis Studies
Hyperlipidemic backgrounds (ApoE knockout, LDLR knockout) combined with dietary or genetic modifications targeting specific pathways.
Heart Failure Studies
Surgical interventions (TAC, MI), genetic cardiomyopathy models, or aging combined with metabolic stress.
Hypertension Studies
Angiotensin system modifications, renal models, or genetic approaches targeting blood pressure regulatory pathways.
Model Types for Cardiovascular Research
Atherosclerosis Models
Atherosclerosis modeling requires hyperlipidemic backgrounds that develop vascular lesions:
ApoE Knockout
The most widely used atherosclerosis model. ApoE deficiency causes severe hypercholesterolemia and spontaneous atherosclerosis that accelerates on Western diet. Lesions develop in the aortic root, brachiocephalic artery, and other large vessels.
LDLR Knockout
LDL receptor deficiency requires Western diet to develop significant hypercholesterolemia and atherosclerosis. This model more closely resembles human familial hypercholesterolemia and is sensitive to dietary intervention.
ApoE/LDLR Double Knockout
Combined deficiency produces more severe hyperlipidemia and accelerated atherosclerosis. Useful when aggressive lesion development is required.
Conditional Atherosclerosis Models
Tissue specific or inducible deletion of atherosclerosis modifying genes on hyperlipidemic backgrounds enables dissection of cell type specific contributions to disease.
Learn moreHeart Failure and Cardiomyopathy Models
Genetic models complement surgical approaches for heart failure research:
Sarcomeric Protein Mutations
Knockin mice expressing mutations in MYH7, MYBPC3, TNNT2, and other sarcomeric genes model hypertrophic and dilated cardiomyopathies. These models enable study of mutation specific disease mechanisms and therapeutic testing.
Signaling Pathway Modifications
Knockout or overexpression of genes in calcium handling, beta adrenergic signaling, or metabolic pathways produce cardiac phenotypes ranging from hypertrophy to heart failure.
Conditional Cardiac Models
Cardiomyocyte specific Cre drivers (alphaMHC Cre, cTNT Cre) enable cardiac specific gene manipulation without systemic effects.
Hypertension Models
Blood pressure regulation involves multiple organ systems:
Renin Angiotensin System
Knockout or overexpression of angiotensinogen, renin, ACE, or angiotensin receptors enables study of this central blood pressure regulatory system.
Renal Sodium Handling
Modifications to ENaC, WNK kinases, and other renal sodium transporters affect blood pressure through volume regulation.
Vascular Tone Regulators
eNOS knockout and other vascular modifying genes affect peripheral resistance and blood pressure.
Lipid Metabolism Models
Understanding lipid handling is central to cardiovascular disease:
Lipoprotein Metabolism
Knockout or humanization of apolipoproteins, lipoprotein receptors, and lipid transfer proteins enables study of cholesterol and triglyceride metabolism.
Hepatic Lipid Handling
Liver specific knockouts of genes involved in lipid synthesis, storage, and export reveal hepatic contributions to systemic lipid levels.
Reverse Cholesterol Transport
ABCA1, ABCG1, SR-BI, and other genes involved in HDL metabolism and cholesterol efflux influence atherosclerosis susceptibility.
Model Design Considerations
Background Strain Selection
Cardiovascular phenotypes are strongly influenced by genetic background:
C57BL/6
Susceptible to atherosclerosis and diet induced metabolic dysfunction. The most common background for cardiovascular studies. However, C57BL/6J carries the Nnt mutation affecting glucose metabolism.
BALB/c
Relatively resistant to atherosclerosis compared to C57BL/6. May be useful for studies requiring less aggressive disease progression.
DBA/2
Distinct cardiac phenotypes and response to cardiac stress compared to C57BL/6. Consider for specific cardiac physiology studies.
129
ES cell donor strains carry varying degrees of 129 background that can influence cardiovascular phenotypes. Backcrossing to pure backgrounds eliminates these effects.
Achieving Clinically Relevant Phenotypes
Several strategies enhance translational relevance:
Dietary Intervention
Western diet (high fat, high cholesterol) accelerates atherosclerosis and metabolic dysfunction. Diet composition significantly affects phenotype severity.
Aging
Many cardiovascular phenotypes require aging for full development. Plan studies with appropriate timelines for aged cohorts.
Combined Risk Factors
Combining genetic modifications (e.g., hyperlipidemia plus hypertension) can produce more severe or clinically relevant phenotypes.
Sex as a Variable
Cardiovascular disease incidence and mechanisms differ between sexes. Include both male and female cohorts and analyze sex specific effects.
Tissue Specific Approaches
Cardiovascular diseases involve multiple cell types and tissues:
| Cre Driver | Target | Applications |
|---|---|---|
| alphaMHC Cre / cTNT Cre | Cardiomyocytes | Heart specific studies |
| Tie2 Cre / VE Cadherin Cre / Cdh5 CreERT2 | Vascular Endothelium | Endothelial cells throughout vasculature |
| SM22 Cre / SMA Cre | Vascular Smooth Muscle | Vessel wall biology |
| LysM Cre | Myeloid Cells | Atherosclerosis and cardiac inflammation |
| Albumin Cre | Hepatocytes | Liver lipoprotein metabolism |
Phenotyping Cardiovascular Models
Atherosclerosis Assessment
Lesion Quantification
En face Oil Red O staining of aorta for total lesion area. Serial sectioning of aortic root for lesion size and composition.
Lesion Composition
Immunohistochemistry for macrophages (MOMA2, CD68), smooth muscle cells (SMA), collagen (Masson trichrome), and lipid content.
Plasma Lipids
Total cholesterol, triglycerides, HDL, and LDL quantification. Lipoprotein profiling by FPLC.
Inflammatory Markers
Circulating cytokines, chemokines, and inflammatory cell populations by flow cytometry.
Cardiac Function Assessment
Echocardiography
Non invasive assessment of ejection fraction, fractional shortening, wall thickness, and chamber dimensions.
Hemodynamic Measurements
Invasive pressure volume loop analysis for detailed assessment of systolic and diastolic function.
ECG
Rhythm assessment, conduction intervals, and arrhythmia detection.
Exercise Testing
Treadmill or voluntary running wheel assessment of exercise capacity and cardiac reserve.
Vascular Function Assessment
Wire Myography
Isolated vessel ring preparations for assessment of vasoconstriction and endothelium dependent or independent relaxation.
Blood Pressure
Tail cuff plethysmography or telemetry for blood pressure measurement.
Vascular Imaging
Ultrasound assessment of vessel wall thickness and blood flow.
Complex Cardiovascular Model Design
Many cardiovascular studies require sophisticated genetic systems:
Conditional Deletion on Hyperlipidemic Background
Floxed alleles crossed to ApoE or LDLR knockout backgrounds enable atherosclerosis studies with cell type specific gene deletion.
Inducible Cardiac Models
Tamoxifen inducible cardiomyocyte Cre (alphaMHC CreERT2) enables temporal control of cardiac gene deletion, avoiding developmental effects.
Reporter Integration
Fluorescent reporters in cardiomyocytes, endothelial cells, or smooth muscle enable lineage tracing and cell population identification.
Humanized Targets
Human gene expression enables testing of therapeutic antibodies or compounds designed for human targets.
Selected Publications in Cardiovascular Research
According to PubMed, recent publications demonstrate the utility of genetically engineered mouse models in cardiovascular research:
Chen H et al. (2025).
Novel Mouse Model of Coronary Atherosclerosis With Myocardial Infarction: Insights Into Human CAD. ↗Circulation Research 136(7): 679-692
Xiao Y et al. (2025).
The innate immune receptor NLRX1 is a novel required modulator for mPTP opening: implications for cardioprotection. ↗Basic Research in Cardiology 120(4): 617-634
Meng Z et al. (2024).
Adipose transplantation improves metabolism and atherosclerosis but not perivascular adipose tissue abnormality or vascular dysfunction in lipodystrophic Seipin null mice. ↗American Journal of Physiology Cell Physiology 326(5): C1356-C1368
What Researchers Say
“iTL generated our angiotensin II type 1a receptor conditional mouse. We found this company very responsive. The project started with discussions on possible construct designs. Following approval, a project manager sent monthly reports alerting us to project milestones. Our experience with iTL was so positive that we have generated more conditional mice with them.”
— Debra Rateri, BS
University of Kentucky
Start Your Cardiovascular Model Project
Our scientific consultants are ready to discuss your cardiovascular research requirements and recommend the optimal model design for your program. Initial consultation is provided at no charge and includes target analysis, strain background recommendations, and timeline estimates.
Frequently Asked Questions
Cardiovascular Research Insights
Subscribe to Lab Signals for expert insights on cardiovascular mouse models, heart disease research, and vascular biology from our PhD scientists.