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Diabetic mouse angiopathy is linked to progressive sympathetic receptor deletion coupled to an enhanced caveolin-1
Mariarosaria Bucci1, Fiorentina Roviezzo, Vincenzo Brancaleone
1Department of Experimental Pharmacology, Faculty of Pharmacy, University of Naples, Italy.
Objective:
Clinical studies have demonstrated that hyperglycaemia represents a major risk factor in the development of the endothelial impairment in diabetes, which is the first step in vascular dysfunction. Using non-obese diabetic mice, we have evaluated the role of the adrenergic system and eNOS on progression of the disease
Methods And Results:
When glycosuria is high (20 to 500 mg/dL), there is a selective reduction in the response to alpha1 and beta2 agonists but not to dopamine or serotonin. When glycosuria is severe (500 to 1000 mg/dL), there is a complete ablation of the contracture response to the alpha1 receptor agonist stimulation and a marked reduced response to beta2 agonist stimulation. This effect is coupled with a reduced expression of alpha1 and beta2 receptors, which is caused by an inhibition at transcriptional level as demonstrated by RT-PCR. In the severe glycosuria (500 to 1000 mg/dL), although eNOS expression is unchanged, caveolin-1 expression is significantly enhanced, indicating that high glucose plasma levels cause an upregulation of the eNOS endogenous inhibitory tone. These latter results correlate with functional data showing that in severe glycosuria, there is a significant reduction in acetylcholine-induced vasodilatation.
Conclusions:
Our results show that in diabetes development, there is a progressive selective downregulation of the alpha1 and beta2 receptors. At the same time, there is an increased expression of caveolin-1, the endogenous eNOS inhibitory protein. Thus, caveolin-1 could represent a new possible therapeutic target in vascular impairment associated with diabetes.
Insights
Hyperglycemia in diabetes progressively impairs vascular function by downregulating alpha1 and beta2 receptors and increasing caveolin-1, a key inhibitor of eNOS. This suggests caveolin-1 as a therapeutic target for diabetic vascular complications.
Area of Science:
- Endocrinology
- Vascular Biology
- Pharmacology
Background:
- Hyperglycemia is a primary risk factor for endothelial dysfunction in diabetes, initiating vascular impairment.
- The adrenergic system and endothelial nitric oxide synthase (eNOS) play critical roles in diabetes progression.
Purpose of the Study:
- To investigate the roles of the adrenergic system and eNOS in the progression of diabetic vascular disease using non-obese diabetic mice.
- To elucidate the molecular mechanisms underlying adrenergic receptor dysfunction and endothelial impairment in diabetes.
Main Methods:
- Utilized non-obese diabetic mouse models with varying levels of glycosuria.
- Assessed adrenergic receptor function through agonist stimulation and receptor expression via RT-PCR.
- Measured eNOS and caveolin-1 expression and evaluated acetylcholine-induced vasodilation.
Main Results:
- High glycosuria selectively reduced responses to alpha1 and beta2 agonists, with severe glycosuria causing complete ablation of alpha1 and reduced beta2 responses.
- Receptor expression decreased at the transcriptional level, indicating downregulation.
- Severe glycosuria increased caveolin-1 expression without altering eNOS, suggesting enhanced endogenous eNOS inhibition.
- Acetylcholine-induced vasodilation was significantly reduced in severe glycosuria.
Conclusions:
- Diabetes leads to progressive, selective downregulation of alpha1 and beta2 receptors.
- Increased caveolin-1 expression in diabetes enhances endogenous eNOS inhibition.
- Caveolin-1 emerges as a potential therapeutic target for managing diabetic vascular impairment.
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