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Effect of glycated LDL on microvascular tone in mice: a comparative study with LDL modified in vitro or isolated from
P Nivoit1, N Wiernsperger, P Moulin
1Diabetic Microangiopathy Research Unit, MERCK Santé-INSERM UMR 585 INSA-Lyon, Villeurbanne, Cedex, France. pierre.nivoit@insa-lyon.fr
Aims/Hypothesis:
In vitro studies have suggested that glycation of LDL might be implicated in diabetic microangiopathy. We therefore investigated the in vivo effects of LDL glycated in vitro on the mouse skeletal muscle arteriolar tone. Since glycation naturally occurs during diabetes, we also tested the effects of LDL isolated from diabetic patients.
Methods:
In anaesthetized mice, the spinotrapezius muscle microcirculation was observed, in situ, using the orthogonal polarization spectral imaging technology. The diameter of terminal (<20 microm) and small arterioles (20-40 microm) was measured before and after a bolus intravenous injection of glycated LDL followed by a continuous perfusion (115 micro g/kg/min).
Results:
A slight decrease of terminal and small arterioles diameter (<10%) was observed with native LDL and LDL isolated from healthy subjects. In contrast, mildly glycated LDL induced a clear vasoconstriction of arterioles (>15%), which was further increased when highly glycated LDL was perfused (>22%). LDL isolated from diabetic patients mimicked the vasoconstriction obtained with in vitro mildly glycated LDL, which underwent similar glycation as those isolated from diabetic patients.
Conclusion/Interpretation:
Our results show in vivo that acute perfusion of both types of glycated LDL (artificially or naturally modified), cause major microvascular modification by enhancing arteriolar tone in skeletal muscle. These findings highlight a new role of glycated LDL at the level of microvessels. We suggest that glycation of LDL could contribute to the impaired vascular reactivity observed in diabetes.
Insights
Glycated LDL, both artificially modified and from diabetic patients, constricts mouse skeletal muscle arterioles in vivo. This suggests LDL glycation contributes to impaired vascular reactivity in diabetes.
Area of Science:
- Cardiovascular Research
- Diabetic Complications
- Microcirculation Studies
Background:
- In vitro studies suggest LDL glycation contributes to diabetic microangiopathy.
- Diabetic patients exhibit naturally occurring LDL glycation.
Purpose of the Study:
- To investigate the in vivo effects of glycated LDL on mouse skeletal muscle arteriolar tone.
- To compare the effects of in vitro glycated LDL with LDL isolated from diabetic patients.
Main Methods:
- In vivo observation of mouse spinotrapezius muscle microcirculation using orthogonal polarization spectral imaging.
- Measurement of arteriolar diameter before and after intravenous injection and perfusion of native, glycated, and patient-derived LDL.
Main Results:
- Mildly glycated LDL induced >15% vasoconstriction; highly glycated LDL induced >22% vasoconstriction.
- LDL from diabetic patients mimicked the vasoconstriction of mildly glycated LDL.
- Native LDL and LDL from healthy subjects caused minimal arteriolar diameter decrease (<10%).
Conclusions:
- In vivo perfusion of glycated LDL (artificial or natural) significantly enhances arteriolar tone in skeletal muscle.
- Glycated LDL plays a role in microvascular dysfunction.
- LDL glycation may contribute to impaired vascular reactivity in diabetes.
