Haemodynamical stress in mouse aortic arch with atherosclerotic plaques: Preliminary study of plaque progression

Atherosclerotic plaques develop at particular sites in the arterial tree, and this regional localisation depends largely on haemodynamic parameters (such as wall shear stress; WSS) as described in the literature. Plaque rupture can result in heart attack or stroke and hence understanding the development and vulnerability of atherosclerotic plaques is critically important. The purpose of this study is to characterise the haemodynamics of blood flow in the mouse aortic arch using numerical modelling. The geometries are digitalised from synchrotron imaging and realistic pulsatile blood flow is considered under rigid wall assumptions. Two cases are considered; arteries with and without plaque. Mice that are fed under fat diet present plaques in the aortic arch whose size is dependent on the number of weeks under the diet. The plaque distribution in the region is however relatively constant through the different samples. This result underlines the influence of the geometry and consequently of the wall shear stresses for plaque formation with plaques growing in region of relative low shear stresses. A discussion of the flow field in real geometry in the presence and absence of plaques is conducted. The presence of plaques was shown to alter the blood flow and hence WSS distribution, with regions of localised high WSS, mainly on the wall of the brachiocephalic artery where luminal narrowing is most pronounced. In addition, arch plaques are shown to induce recirculation in the blood flow, a phenomenon with potential influence on the progression of the plaques. The oscillatory shear index and the relative residence time have been calculated on the geometry with plaques to show the presence of this recirculation in the arch, an approach that may be useful for future studies on plaque progression

Altered ureteric branching morphogenesis and nephron endowment in offspring of diabetic and insulin-treated pregnancy

<div><p>There is strong evidence from human and animal models that exposure to maternal hyperglycemia during <i>in utero</i> development can detrimentally affect fetal kidney development. Notwithstanding this knowledge, the precise effects of diabetic pregnancy on the key processes of kidney development are unclear due to a paucity of studies and limitations in previously used methodologies. The purpose of the present study was to elucidate the effects of hyperglycemia on ureteric branching morphogenesis and nephrogenesis using unbiased techniques. Diabetes was induced in pregnant C57Bl/6J mice using multiple doses of streptozotocin (STZ) on embryonic days (E) 6.5-8.5. Branching morphogenesis was quantified <i>ex vivo</i> using Optical Projection Tomography, and nephrons were counted using unbiased stereology. Maternal hyperglycemia was recognised from E12.5. At E14.5, offspring of diabetic mice demonstrated fetal growth restriction and a marked deficit in ureteric tip number (control 283.7±23.3 vs. STZ 153.2±24.6, mean±SEM, <i>p</i>&lt;0.01) and ureteric tree length (control 33.1±2.6 mm vs. STZ 17.6±2.7 mm, <i>p</i> = 0.001) vs. controls. At E18.5, fetal growth restriction was still present in offspring of STZ dams and a deficit in nephron endowment was observed (control 1246.2±64.9 vs. STZ 822.4±74.0, <i>p&lt;</i>0.001). Kidney malformations in the form of duplex ureter and hydroureter were a common observation (26%) in embryos of diabetic pregnancy compared with controls (0%). Maternal insulin treatment from E13.5 normalised maternal glycaemia but did not normalise fetal weight nor prevent the nephron deficit. The detrimental effect of hyperglycemia on ureteric branching morphogenesis and, in turn, nephron endowment in the growth-restricted fetus highlights the importance of glycemic control in early gestation and during the initial stages of renal development.</p> </div

Maternal blood glucose concentrations and glomerular number in offspring of E18.5 cohort.

<p>(A) 3 hour fasting blood glucose concentrations of control (solid line, filled square), STZ-treated (dashed line, open square) and STZ+Insulin-treated (dashed line, open circle) dams throughout gestation. (B) Total glomerular number in kidneys of control (clear bar), STZ-treated (striped bar) and STZ+Insulin-treated (solid bar) embryos. Glucose analysis by repeated measures two-way ANOVA for maternal STZ and insulin treatment and time followed by Fishers LSD post hoc analysis; (n)  =  control (11), STZ (8), STZ+Insulin (5). Glomerular number analysis by two-way ANOVA for maternal STZ and insulin treatment and offspring sex followed by Fishers LSD post-hoc analysis; (n)  =  control (7 litters comprising 20 kidneys), STZ (6 litters comprising 14 kidneys), STZ+Insulin (5 litters comprising 10 kidneys). Values are mean±SEM. **<i>p</i>&lt;0.01, ***<i>p</i>&lt;0.001 ****<i>p</i>&lt;0.0001 <i>vs</i>. control.</p

Spearman's rank coefficients: associations between glomerular number and independent variables at E18.5.

<p>Spearman's Rho (top value), <i>p</i> value (bottom value). Negative values indicate a negative association. AUC  =  area under the curve. N_glom =  total estimated glomerular number.</p

Growth parameters of control and STZ-treated embryos at E14.5; and control, STZ and STZ+Insulin-treated embryos at E18.5.

<p>Data from E14.5 and E18.5 cohorts were analysed separately by a linear mixed model with maternal STZ and insulin treatment and offspring sex as independent variables, weighted for litter. Values are mean±SEM. E14.5: (n)  =  control (n =  5 litters comprising 41 embryos), STZ-treated (n = 5 litters comprising 33 embryos). E18.5: (n)  =  control (n = 11 litters comprising 72 embryos), STZ (n = 10 litters comprising 41 embryos), STZ+Insulin (n = 5 litters comprising 25 embryos).</p

Spearman's rank coefficients: associations between measures of ureteric tree development and independent variables at E14.5.

<p>Spearman's Rho (top value), <i>p</i> value (bottom value). Negative values indicate a negative association. AUC  =  area under the curve.</p