Abstract W P391: Obesity Causes Endothelium Dysfunction in Rat Cerebral Parenchymal Arterioles

Abstract

Obesity is a risk factor for dementia. The diameter and dilatory ability of cerebral parenchymal arterioles (PAs) regulates local perfusion to discrete neuronal populations matching nutrient delivery to neuronal demand. A mismatch in this process could lead to neuronal loss and dementia development. Thus, we hypothesized that feeding rats a high-fat (HF) diet would impair endothelium-dependent dilation and cause inward remodeling of PAs. Three-week-old male Sprague-Dawley rats were fed a HF diet for 17 weeks. Rats fed regular chow were controls. PAs branching from the middle cerebral artery were isolated and cannulated in a pressure myograph, and pressurized to 50mmHg. After the development of spontaneous myogenic tone endothelium-dependent dilation was assessed with carbachol (1nM - 100μM). PAs were then placed in 0Ca2+-PSS with 2mM EGTA+100μM sodium nitroprusside to assess of passive diameter and wall thickness. Data are means±SEM, Control vs. HF (n=3 in each group). Myogenic tone generation (% tone: 27.5±2.9 vs 22.8±2.2, p=0.12) and PA resting diameters (50.7±3.7 vs. 51.5±2.9μm, p=0.43) were not different between HF and control rats. PAs from HF rats showed a marked reduction in dilation to carbachol (change in diameter from baseline at 100μM: 5.3±0.7 vs. 1.1±0.7μm, p=0.01) and a trend towards an increase in the logEC50 (-7.2±0.2 vs. -5.9±0.8, p=0.08). No changes were observed in PAs passive lumen diameter (70.5±1.8 vs. 69.6±6.6μm, p=0.45) or wall thickness (5.3±0.4 vs. 5.2±0.8μm, p=0.46). These data suggest blood flow regulation to the parenchyma may be impaired in obese rats. Therefore we assessed the mRNA expression of proteins that have been linked to neuronal health and blood brain barrier function (n=6-8 in each group). Cortical mRNA expression of doublecortin, a marker of new neurons, was reduced by 38.8±9.4% (p<0.05) in HF rats. In HF rats the mRNA expression of synaptophysin, a marker of synapses, was reduced by 45.7±13.5% (p<0.05), and the expression of claudin 5; a blood brain barrier protein was reduced by 16.0±8.5% (p<0.05). These data suggest that diet-induced obesity causes endothelial dysfunction in PAs from rats, and that this leads to impaired neuronal and blood brain barrier function that could potentially culminate in dementia.