Influence of Type II Diabetes on Arterial Tone and Endothelial Function in Murine Mesenteric Resistance Arteries

Abstract

An arteriograph was used to assess myogenic tone, smooth muscle contractility and the influence of endothelial function on mesenteric resistance artery reactivity in insulin-resistant mice (C57BL/KsJ-db/db) and age- and gender-matched wild-type mice. Increases in transmural pressure induced myogenic tone in arteries from both control and db/db mice. At 12 and 16 weeks of age, greater tone developed in diabetic than in control mice. In control, but not in db/db mice, pretreatment of arteries with L-NAME potentiated myogenic tone. Indomethacin and SQ29548 (PGH₂/TXA₂ receptor antagonist) had no efffect in control, but inhibited myogenic tone in db/db mice. Endothelium-dependent vasodilation induced by acetylcholine and bradykinin, was depressed in db/db mice and potentiated by SQ29548 and LY333531 (protein kinase C_β inhibitor). Messenger RNA expression levels for PKC_β were over-expressed 2.5-fold in db/db relative to those in control mice. However, expression levels of mRNA for eNOS, PKC_α, and PKC_ξ were similar in the db/db and control mice. Collectively, these results suggest that the greater myogenic tone in resistance arteries from diabetic mice may be attributable, to greater amounts of one or more vasoconstricting prostanoids. Our data indicate that in diabetic mice, basal and agonist-stimulated NO releases are depressed and NO-mediated vasorelaxation in these mice may be countered by an endogenous vasoconstrictive prostanoid. This prostanoid-induced vasoconstriction is mediated by a PKC_β-dependent mechanism. Therefore, heightened activation of PKC_β and release of a vasoconstrictor prostanoid could play a role in endothelial dysfunction associated with type II diabetes.

Myogenic tone and reactivity of cerebral arteries in Type II diabetic BBZDR/Wor rat

“…In contrast, arteries from obese diabetic rats showed either similar or higher myogenic tone with the advanced age and acquired the ability to withstand higher pressures with no forced dilation, resulting in a defective pressure-mediated autoregulation of blood flow to the brain. Enhanced myogenic constriction observed in this model is consistent with the available few reports in type II diabetes, namely, in mesenteric arteries from mouse model of type II diabetes (Lagaud et al, 2001) and skeletal muscle arterioles from Zucker rat model of obesity-induced type II diabetes (Frisbee et al, 2002). In contrary, we observed decreased pressure-induced in the ophthalmic artery of BBZDR/Wor rat and the decrease was endothelium-dependent (Ito et al, 2006), suggesting vascular beddependent variation in the effect of type II diabetes on pressure-dependent autoregulation.…”

“…Endothelium-dependent dilation in mesenteric arteries was shown to be unaffected in obese Zucker rat (Bohlen and Lash, 1995) and decreased in mesenteric (Lagaud et al, 2001) and cerebral arteries (Didion et al, 2005) of db/db mice. Almost with no exception, studies that have shown impaired endotheliumdependent relaxation in experimental diabetes, have found normal relaxation to nitrovasodilators or agents that release nitric oxide spontaneously.…”

“…Arteriolar hypo-and hyper-responsiveness to endogenous vasodilators and constrictors have been reported in conduit and resistance arteries in diabetic models but very few studies have been focused on myogenic tone (Pieper, 1998). Increased myogenic tone was observed in cerebral arteries from streptozotocin-induced type I diabetic rats (Zimmermann et al, 1997), in mesenteric arteries of db/db mice (Lagaud et al, 2001) and in skeletal muscle arterioles of obese Zucker rats (Frisbee et al, 2002) and streptozotocin-induced type I diabetic rats (Ungvari et al, 1999).…”

Glucosamine-Induced Endoplasmic Reticulum Dysfunction Is Associated With Accelerated Atherosclerosis in a Hyperglycemic Mouse Model

“…AGEs induce intracellular inflammatory and oxidative stress pathways through interactions with receptors for AGEs (RAGEs) (4). Protein kinase C can be activated by AGE-RAGE interactions, resulting in proatherogenic consequences, including disruption of vascular structure and response as well as enhanced inflammatory gene expression (5,6). However, the apparent inability of antioxidant supplementation to reduce cardiovascular events in diabetic patients suggests that alternative mechanisms of hyperglycemia-induced atherosclerosis may also contribute to the progression of atherosclerosis (7)(8)(9)(10).…”

Cerebrovascular Dysfunction in Zucker Obese Rats Is Mediated by Oxidative Stress and Protein Kinase C

“…However, the in vitro nature of these experiments prevented the analysis of the IR-induced mechanisms of cerebrovascular dysfunction. These pathological alterations possibly involve protein kinase C (PKC) activation and production of superoxide anion (O 2 Ϫ* ), which are key factors in the development of endothelial dysfunction and reduced nitric oxide (NO)-mediated relaxation in the peripheral and coronary circulations (8,(22)(23)(24)(25)(26). In addition, these same mechanisms might also impair K ϩ channel-mediated dilator responses in IR, since they were shown to inhibit K ϩ channel function in other vascular diseases (27)(28)(29)(30).…”