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Quantitative Analysis of Cellular Composition in Advanced Atherosclerotic Lesions of Smooth Muscle Cell Lineage-Tracing Mice
Published on: February 20, 2019
Smooth Muscle Cell Notch2 Is Not Required for Atherosclerotic Plaque Formation in ApoE Null Mice
Jessica Davis-Knowlton1,2, Jacqueline E Turner1, Anne Harrington1
1Center for Molecular Medicine, MaineHealth Institute for Research, MaineHealth, Scarborough, Maine, USA.
Introduction:
We previously identified Notch2 in smooth muscle cells (SMC) in human atherosclerosis and found that signaling via Notch2 suppressed human SMC proliferation. Thus, we tested whether loss of Notch2 in SMC would alter atherosclerotic plaque progression using a mouse model.
Methods:
Atherogenesis was examined at the brachiocephalic artery and aortic root in a vascular SMC null (inducible smooth muscle myosin heavy chain Cre) Notch2 strain on the ApoE-/- background. We measured plaque morphology and size, as well as lipid, inflammation, and smooth muscle actin content after Western diet.
Results:
We generated an inducible SMC Notch2 null on the ApoE-/- background. We observed ∼90% recombination efficiency with no detectable Notch2 in the SMC. Loss of SMC Notch2 did not significantly change plaque size, lipid content, necrotic core, or medial area. However, loss of SMC Notch2 reduced the contractile SMC in brachiocephalic artery lesions and increased inflammatory content in aortic root lesions after 6 weeks of Western diet. These changes were not present with loss of SMC Notch2 after 14 weeks of Western diet.
Conclusions:
Our data show that loss of SMC Notch2 does not significantly reduce atherosclerotic lesion formation, although in early stages of plaque formation there are changes in SMC and inflammation.
Insights
Loss of Notch2 in smooth muscle cells (SMC) did not significantly alter atherosclerosis progression. Early plaque development showed changes in SMC and inflammation, but these effects were transient.
Area of Science:
- Cardiovascular Biology
- Cell Signaling
- Atherosclerosis Research
Background:
- Notch2 signaling in smooth muscle cells (SMC) suppresses proliferation in human atherosclerosis.
- Understanding Notch2's role in SMC is crucial for atherosclerosis research.
Purpose of the Study:
- To investigate the impact of Notch2 loss in SMC on atherosclerotic plaque progression.
- To utilize a mouse model to study the in vivo function of Notch2 in SMC during atherogenesis.
Main Methods:
- Generated an inducible SMC-specific Notch2 knockout mouse model on an ApoE-/- background.
- Examined atherogenesis in the brachiocephalic artery and aortic root under Western diet.
- Assessed plaque morphology, size, lipid, inflammation, and smooth muscle actin content.
Main Results:
- Loss of SMC Notch2 did not significantly alter overall plaque size, lipid content, or necrotic core.
- Early (6-week) Western diet feeding revealed reduced contractile SMC and increased inflammation in lesions upon Notch2 loss.
- These early-stage alterations were not observed at later time points (14 weeks).
Conclusions:
- Loss of Notch2 in SMC does not significantly impede atherosclerotic lesion formation.
- Transient changes in SMC phenotype and inflammation occur in early plaque development without Notch2.
- The role of Notch2 in SMC during atherosclerosis appears to be stage-dependent.
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