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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:721.)
© 2004 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Diabetic Mouse Angiopathy Is Linked to Progressive Sympathetic Receptor Deletion Coupled to an Enhanced Caveolin-1 Expression

Mariarosaria Bucci; Fiorentina Roviezzo; Vincenzo Brancaleone; Michelle I. Lin; Annarita Di Lorenzo; Carla Cicala; Aldo Pinto; William C. Sessa; Silvana Farneti; Stefano Fiorucci; Giuseppe Cirino

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.

Correspondence to Dr Giuseppe Cirino, Professor of Pharmacology, Department of Experimental Pharmacology, University of Naples, Federico II, via Domenico Montesano 49, 80131 Naples, Italy. 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 ß₂ 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 ß₂ agonist stimulation. This effect is coupled with a reduced expression of ₁ and ß₂ 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 ß₂ 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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