Interaction between maternal and offspring diet to impair vascular function and oxidative balance in high fat fed male mice.

AIMS: To determine the impact of maternal and post-weaning consumption of a high fat diet on endothelium-dependent vasorelaxation and redox regulation in adult male mouse offspring. METHODS: Female C57BL6J mice were fed an obesogenic high fat diet (HF, 45% kcal fat) or standard chow (C, 21% kcal fat) pre-conception and throughout pregnancy and lactation. Post-weaning, male offspring were continued on the same diet as their mothers or placed on the alternative diet to give 4 dietary groups (C/C, HF/C, C/HF and HF/HF) which were studied at 15 or 30 weeks of age. RESULTS: There were significant effects of maternal diet on offspring body weight (p<0.004), systolic blood pressure (p = 0.026) and endothelium-dependent relaxation to ACh (p = 0.004) and NO production (p = 0.005) measured in the femoral artery. With control for maternal diet there was also an effect of offspring post-weaning dietary fat to increase systolic blood pressure (p<0.0001) and reduce endothelium-dependent relaxation (p = 0.022) and ACh-mediated NO production (p = 0.007). There was also a significant impact of age (p<0.005). Redox balance was perturbed, with altered regulation of vascular enzymes involved in ROS/NO signalling. CONCLUSIONS: Maternal consumption of a HF diet is associated with changes in vascular function and oxidative balance in the offspring of similar magnitude to those seen with consumption of a high fat diet post-weaning. Further, this disadvantageous vascular phenotype is exacerbated by age to influence the risk of developing obesity, raised blood pressure and endothelial dysfunction in adult life.

Maternal high-fat feeding primes steatohepatitis in adult mice offspring, involving mitochondrial dysfunction and altered lipogenesis gene expression.

UNLABELLED: Nonalcoholic fatty liver disease (NAFLD) describes an increasingly prevalent spectrum of liver disorders associated with obesity and metabolic syndrome. It is uncertain why steatosis occurs in some individuals, whereas nonalcoholic steatohepatitis (NASH) occurs in others. We have generated a novel mouse model to test our hypothesis: that maternal fat intake contributes to the development of NAFLD in adult offspring. Female mice were fed either a high-fat (HF) or control chow (C) diet before and during gestation and lactation. Resulting offspring were fed either a C or a HF diet after weaning, to generate four offspring groups; HF/HF, HF/C, C/HF, C/C. At 15 weeks of age, liver histology was normal in both the C/C and HF/C offspring. Kleiner scoring showed that although the C/HF offspring developed nonalcoholic fatty liver, the HF/HF offspring developed NASH. At 30 weeks, histological analysis and Kleiner scoring showed that both the HF/C and C/HF groups had NAFLD, whereas the HF/HF had a more severe form of NASH. Therefore, exposure to a HF diet in utero and during lactation contributes toward NAFLD progression. We investigated the mechanisms by which this developmental priming is mediated. At 15 weeks of age, hepatic mitochondrial electron transport chain (ETC) enzyme complex activity (I, II/III, and IV) was reduced in both groups of offspring from HF-fed mothers (HF/C and HF/HF). In addition, measurement of hepatic gene expression indicated that lipogenesis, oxidative stress, and inflammatory pathways were up-regulated in the 15-week-old HF/C and HF/HF offspring. CONCLUSION: Maternal fat intake contributes toward the NAFLD progression in adult offspring, which is mediated through impaired hepatic mitochondrial metabolism and up-regulated hepatic lipogenesis.

The normal cellular prion protein and its possible role in angiogenesis.

Cellular Prion Protein (PrPc) is a ubiquitous glycoprotein present on the surface of endothelial cells. Resting vascular endothelial cells show minimum expression of PrPc and can constitutively release PrPc. PrPc participates in cell survival, differentiation and angiogenesis. During development, neonatal brain endothelial cells transiently express PrPc. Our group recently reported upregulation of PrPc in microvessels from ischemic brain regions in stroke patients. Ischemia/hypoxia induces PrPc expression through the activation of extracellular signal-regulated kinase (ERK). All these data suggest that PrPc plays an important role in angiogenic responses. In addition, PrPc participates in cellular function in the central nervous system, since PrPc is also highly expressed in neurons. PrPc binds copper, suggesting a role in copper metabolism. PrPc also protects cells against oxidative stress and it seems to be involved in neuroprotection. Several studies have demonstrated that PrPc prevents cells from apoptosis and subsequent tissue damage. Moreover, PrPc plays an important role in the immune response. Here, we review the multiple functions of PrPc with a special attention to its recently reported role in angiogenesis.

Dynamin and perforin are associated with neovascularisation in advanced carotid plaques.

Intimal plaque neovascularization is associated with the development of symptomatic disease and thrombosis, with new 'leaky' fragile microvessels prone to haemorrhage. Perforin or pore forming protein is involved in vascular cell death by forming pores in target cells. Enzymes, in particular, granzyme B are secreted by immune infiltrates present in inflammatory plaque regions and have been shown to induce endothelial cell apoptosis. Similarly, dynamin-2 is a GTPase which mediates oxidised low density lipoprotein-induced apoptosis and is also required for granzyme B-mediated exocytosis and apoptosis. Our pilot studies identified increased expression of these proteins in complicated atherosclerotic plaques. Here we demonstrate by immunohistochemistry that both proteins are over-expressed in angiogenic regions of complicated carotid plaques. Dynamin-2 was extensively localised around microvessels and in immune infiltrating cells whilst perforin was localised in immune infiltrating cells, endothelial cells and smooth muscle cells. Over-expression of these proteins may contribute to plaque destabilisation by increasing cellular apoptosis in vulnerable atherosclerotic plaques.

Changes in Hyaluronan Metabolism and RHAMM Receptor Expression Accompany Formation of Complicated Carotid Lesions and May be Pro-Angiogenic Mediators of Intimal Neovessel Growth.

Previous studies have shown that changes in expression of the glycosaminoglycan, hyaluronan (HA) were associated with erosion in areas of post-mortem coronary artery liable to rupture. Angiogenesis is an important feature of ulcerating haemorrhagic plaques prone to rupture. HA is a glycosaminoglycan known to possess potent angiogenic properties on metabolism to oligosaccharides of HA (o-HA) in the presence of hyaluronidase (HYAL) enzymes. In this study, we have examined HA receptor and HYAL enzyme expression in a series of carotid artery specimens used as vascular transplants and exhibiting various stages of atherosclerotic lesions as determined by anatomo-pathology. Our results demonstrated dramatically increased expression of HYAL-1 in regions of inflammation associated with complicated plaques. Receptor for HA-mediated motility (RHAMM), which is known to be important in transducing angiogenic signals in vascular endothelium, was strongly expressed on intimal blood vessels from complicated lesions but almost absent from other regions including adventitial vessels. Metabolism of HA, together with up-regulation of RHAMM in complicated plaque lesions might be partly responsible for over-production of leaky neovessels and predisposition to plaque rupture.