Impaired EDHF-mediated vasodilatation in adult offspring of rats exposed to a fat-rich diet in pregnancy

Increasing evidence supports the concept that windows of vulnerability to adverse environmental stimuli in early life may predispose to adulthood disease (Gluckman & Hanson, 2004). In this study we have carried out a detailed investigation of functional abnormalities in small arteries from adult animals, acquired as a result of developmental ‘programming’ induced by maternal dietary imbalance. Recent epidemiological (Roseboom et al. 2001) and animal studies (Ozaki et al. 2001; Ozanne & Hales, 2002; Khan et al. 2003) have suggested that the cardiovascular risk factors which cluster in the metabolic syndrome, hitherto attributed to genetic and adult environmental influences, can be acquired in utero. These include insulin resistance, hypertension, glucose intolerance, central adiposity and abnormal serum lipid profiles. We have recently developed an animal model in which adult offspring of rats fed a diet rich in saturated fat during pregnancy and suckling develop certain features of the metabolic syndrome including hypertension, dyslipidaemia, adiposity and altered glucose homeostasis (Khan et al. 2003, 2004). In addition, small mesenteric arteries of the offspring demonstrated marked reduction in relaxation in response to the endothelium-dependent agonist acetylcholine. Endothelial dysfunction has been implicated in insulin resistance and atherogenesis and reduced endothelium-dependent relaxation is an independent risk factor for cardiovascular disease and the metabolic syndrome (Bonora et al. 2003). To date, we have established that the defect in relaxation in the mesenteric small arteries cannot be attributable to altered vascular smooth muscle sensitivity to nitric oxide since relaxation in response to exogenously applied NO was unaffected (Khan et al. 2003). The principal purpose of this study was to determine which of the different component pathways of endothelium-dependent dilatation contributes to the failure of endothelial function in the small mesenteric arteries from adult offspring of the fat-fed dams. The relative roles of nitric oxide, prostacyclin and the postulated endothelium-derived hyperpolarizing factor(s) (EDHF) have been studied. Further investigations of constrictor function were also undertaken including responses to angiotensin II, since altered activity of the renin–angiotensin axis has been implicated in other models of developmental programming of hypertension (Langley-Evans et al. 1996; Sahajpal & Ashton, 2003). In addition, in order to determine whether endothelial dysfunction was common to different vascular beds, arteries from the femoral circulation were studied.