Endothelium-dependent impairments to cerebral vascular reactivity with type 2 diabetes mellitus in the Goto-Kakizaki rat

Abstract

Type 2 diabetes mellitus (T2DM) is a prevalent pathology associated with elevated cerebrovascular disease risk. We determined wall mechanics and vascular reactivity in ex vivo middle cerebral arteries (MCA) from male Goto-Kakizaki rats (GK; ~17 wk old) versus control Wistar Kyoto rats (WKY) to test the hypothesis that the diabetic environment in GK, in the absence of obesity and other comorbidities, leads to endothelial dysfunction and impaired vascular tone regulation. Dilation of MCA following challenge with acetylcholine and hypoxia was blunted in MCA from GK versus WKY, due to lower nitric oxide bioavailability and altered arachidonic acid metabolism, whereas myogenic activation and constrictor responses to serotonin were unchanged. MCA wall distensibility and cross-sectional area were not different between GK and WKY, suggesting that wall mechanics were unchanged at this age, supported by the determination that MCA dilation to sodium nitroprusside was also intact. With the use of ex vivo aortic rings as a bioassay, altered vascular reactivity determined in MCA was paralleled by relaxation responses in artery segments from GK, whereas measurements of vasoactive metabolite production indicated a loss of nitric oxide and prostacyclin bioavailability and an increased thromboxane A2 production with both methacholine challenge and hypoxia. These results suggest that endothelium-dependent dilator reactivity of MCA in GK is impaired with T2DM, and that this impairment is associated with the genesis of a prooxidant/pro-inflammatory condition with diabetes mellitus. The restriction of vascular impairments to endothelial function only, at this age and development, provide insight into the severity of multimorbid conditions of which T2DM is only one constituent.

The Potential Role of Irisin in Vascular Function and Atherosclerosis: A Review

“…Previous studies in humans have shown positive correlation between circulating irisin levels and endothelium-dependent vasodilation [ 12 ], flow-mediated dilation [ 24 ], and coronary atherosclerosis index [ 30 ], suggesting irisin may regulate vascular endothelial function. Metabolic dysfunction such as obesity and T2D is associated with endothelial dysfunction characterized by impaired endothelium-dependent vasorelaxation in the experimental rodent models and in humans [ 12 , 40 , 41 , 42 , 43 , 44 ]. Although exogenous irisin has been suggested to increase energy expenditure and reduce high fat diet-induced obesity and insulin resistance [ 1 ], it is still unclear whether exogenous irisin administration ameliorates vascular dysfunction which is induced by abnormal metabolism, and whether irisin may induce vasoconstriction or vasodilation in the vasculature.…”

Cerebral Vascular Tone Regulation: Integration and Impact of Disease

“…In skeletal muscle, dilation from mild hypoxia (15% O 2 ) was mostly NO-dependent, while moderate (10% O 2 ) was mediated by a combination of increased PGI 2 and decreased 20-HETE, and severe (0% O 2 ) was almost entirely accounted for by an increase in PGI 2 [141]. In all cases, there appears to be significant involvement by the endothelium to mediate the dilation, which is further supported by a reduction in hypoxic dilation when isolated vessels were exposed to indomethacin (an inhibitor of AA metabolism and thus the production of PGI 2 ) [137,144,145] and to a lesser degree by L-NAME (an inhibitor of NO production from NOS) [145]. Therefore, PGI 2 is likely a substantial contributor to hypoxic dilation with a lesser but likely still significant role for NO.…”

“…The chronic inflammatory state seen in MetS likely contributes to the reduction in NO bioavailability due to increased scavenging to the produced NO by reactive oxygen species since this reduction in NO bioavailability is consistently reported to evolve in parallel with oxidant stress and the development of a chronic inflammatory state [185,186]. This is supported by improved dilatory reactivity of MCA with the pretreatment of the cell-permeable superoxide dismutase mimetic TEMPOL in a model of T2DM [145]. Interestingly some studies have actually shown an increase in eNOS expression which may be an attempt to compensate for the increased scavenging; however, they too continue to find reduced dilator reactivity [187].…”

“…Aside from reduced NO bioavailability, a shift in arachidonic acid metabolism toward constrictors and away from dilators that are highly responsible for hypoxic dilation has been demonstrated [145]. Thus not only does endothelial dysfunction seen in MetS increase cerebrovascular resistance by decreased dilator metabolite production it may also promote the production of constrictors that exacerbate the impaired dilation capacity of cerebral vessels [184,188].…”

“…For example, studies using SNP, an exogenous NO donor, while blocking endogenous NO production by eNOS using L-NAME, found smaller relaxation of the MCA in spontaneously hypertensive rats which was attributed to a decreased expression of soluble guanylate cyclase [189][190][191][192]. In a model of T2DM decreased sensitivity of MCA to the PGI 2 analog iloprost was also found suggesting that both decrease production and sensitivity of dilators may be contributing to the impaired dilation of the cerebral circulation in MetS [145].…”