Endothelial dysfunction starting in utero: you are what your mother eats?

The in utero nutritional environment affects the phenotype and long-term health of offspring. In humans classic observations from the 1944–45 ‘Dutch Starvation Winter’ at the end of the Second World War suggest that significant nutritional stress in utero can have profound effects on overall health, and may contribute importantly to diseases like hypertension and diabetes in middle-age (Kyle & Pichard 2006). In this context, Rodford et al. (2008) in an article in this issue of The Journal of Physiology demonstrate that an isocaloric but protein restricted diet fed to pregnant rats can cause complex and subtle changes in vascular endothelial function of the offspring. The key finding at a physiological level is reduced vasodilator responses to the endothelial agonist, acetylcholine. This is accompanied by a complex collection of biochemical and molecular events suggesting that the pathways responsible for maintaining appropriate levels of reactive oxygen species (they are not all bad) are disrupted in a way to favour the generation of more reactive oxygen species and perhaps inactivation of or competition with vasodilating factors released by the endothelium. While the rat pups in this study did not develop frank hypertension after birth, and there were no dramatic differences in body weight, the question is whether or not the stage was set in these animals for increased risk for diseases like hypertension and diabetes or other metabolic disorders later in life. All things being equal, the following educated clinical guesses can be made. First, as humans age, their sympathetic nerve traffic goes up. This rise in sympathetic activity is not necessarily associated with a rise in blood pressure. However, there is mounting evidence and it is certainly reasonable to hypothesize that even a small hit to endothelial function in individuals with high levels of sympathetic traffic can tip the balance toward hypertension. In the context of the current study, perhaps the in utero environment has a role in this pathophysiological scenario (Joyner et al. 2007). Second, many humans now live in a high calorie, low physical activity world and evidence of endothelial dysfunction and traditional cardiovascular risk factors once thought to start in middle age are now appearing in younger and younger children and adolescents (Raitakari et al. 2003). If individuals have suffered from marginal nourishment during fetal development, they may be even more susceptible to dietary and lifestyle mediated cardiovascular and metabolic risk factors. This possibility has major public health implications everywhere but especially when there is rapid ‘Westernization’ of diet. While no single thrifty gene has been identified, perhaps fetal under-nutrition operates in a way to generate a functional ‘thrifty gene’ that operates with ‘over-nutrition’ later in life to facilitate development of the so-called metabolic syndrome. Third, while a host of obvious follow-up experiments and other questions stem from the results of this paper (e.g. will the offspring of the protein-restricted mothers have more salt-sensitive blood pressure responses?), perhaps a more important point is that programmes designed to provide comprehensive nutritional and wellness interventions to pregnant women, mothers and children have a long-term positive influence on the ‘health of the offspring’ (Owen & Owen 1997). These programmes, frequently run by nurses and their colleagues in the social services are cost effective, and the need for them has never been greater. In summary, the paper by Rodford and colleagues is an example of an emerging scientific picture that includes data from the genetic and molecular level, animal models, integrative physiology studies in humans, and epidemiological and outcomes data in populations. It is an excellent example of how physiological investigations can help explain complex biological phenomena, raise new questions, and even inform public policy.