on February 12, 2004
Published online before print February 12, 2004, doi: 10.1161/01.ATV.0000122362.44628.09
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Submitted on July 16, 2003
Accepted on December 18, 2003
Diabetic Mouse Angiopathy Is Linked to Progressive Sympathetic Receptor Deletion Coupled to an Enhanced Caveolin-1 Expression
Mariarosaria Bucci ;
From the Department of Experimental Pharmacology (M.B., F.R., V.B., A.D.L., C.C., G.C.), Faculty of Pharmacy, University of Naples, Italy; Boyer Center for Molecular Medicine (M.I.L., W.C.S.), Yale University, New Haven, Conn; Department of Pharmaceutical Sciences (A.P.), Faculty of Pharmacy, University of Salerno, Italy; and Dipartimento di Medicina Sperimentale (S. Farneti, S. Fiorucci), Università di Perugia, Italy.
* To whom correspondence should be addressed. E-mail: cirino{at}unina.it.
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 
1 and 
2 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 1 receptor agonist stimulation and a marked reduced response to 2 agonist stimulation. This effect is coupled with a reduced expression of 1 and 2 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 1 and 2 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.
Key words: eNOS • caveolin-1 • adrenergic system • vascular impairment • diabetes
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