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

Abstract

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

Endothelial dysfunction in diabetic erectile dysfunction

“…47 Bovine aortic endothelial cells cultured in a high glucose environment, as well as aortas isolated from nonobese diabetic mice, exhibit increased caveolin-1 expression. 48 Hsp90 and caveolin-1 expression and their interactions with eNOS have been documented in the rat penis (Musicki et al, unpublished observations and references 14,49,50 ). The penis of the diabetic rat has been reported to contain decreased expression of caveolin-1 compared to that of the nondiabetic rat.…”

Regulation of endothelial derived nitric oxide in health and disease

“…In non-obese diabetic mice, modest hyperglycemia triggers s a selective reduction in the response to alpha1 and beta2 agonists but not to dopamine or serotonin (Bucci et al 2004). When glycosuria is severe (500 to 1000 mg/dl), there is a complete ablation vasoconstrictor responses to the alpha1 receptor agonist stimulation and a marked reduced response to beta2 agonist stimulation.…”

Circulatory and renal consequences of pregnancy in diabetic NOD mice

“…With increasing hyperglycemia, the authors found complete absence of contractile response to adrenergic signaling. However, normoglycemic NOD mice retained vascular reactivity similar to normal mice (CD-1) [22]. Normoglycemic NOD mice proceeded through pregnancy without complication, suggesting that in the disease-free state, neural, cardiovascular and endocrine adaptations are intact.…”

“…This is supported by studies of overtly diabetic non-pregnant NOD mice that links hyperglycemia with vascular dysfunction [22]. Aortic rings from diabetic NOD mice have significantly impaired nitric oxide (NO)-dependent relaxation and vasoconstriction [22]. With increasing hyperglycemia, the authors found complete absence of contractile response to adrenergic signaling.…”

“…The circulatory system of the pregnant diabetic NOD mouse appeared somewhat refractory to adrenergic and RAS signals. This is supported by studies of overtly diabetic non-pregnant NOD mice that links hyperglycemia with vascular dysfunction [22]. Aortic rings from diabetic NOD mice have significantly impaired nitric oxide (NO)-dependent relaxation and vasoconstriction [22].…”