Molecular, cellular and endocrine signalling in the perinatal cardiovascular system: interplay and developmental programming

This themed issue of The Journal of Physiology was developed to include a group of cutting edge articles that discuss recent research into the interplay between the fetal and maternal cardiovascular and endocrine systems and developmental programming. These articles are the result of a meeting of basic and clinical scientists actively involved in research directly related to cardiovascular perinatal biology during pregnancy. The group met in Tucson, AZ on August 14–19, 2004 for the Third Federation of American Societies for Experimental Biology Summer Research Conference on ‘Molecular and Cellular Signalling in the Perinatal Cardiovascular System’. The overall rationale for the meeting was that the mechanisms that control the fetal and maternal cardiovascular, endocrine and metabolic systems during pregnancy are extremely important topics of basic and clinical research with significant health implications. Recent research in this area has emphasized the extraordinary and lifelong consequences of nutritional and pathophysiological influences during early development, which may occur through perturbation of maternal and fetal cardiovascular/endocrine systems. Several major themes emerged from this meeting, too numerous to be adequately covered in detail here. One was the major role of in utero stress or ‘stressors’ in altering the development and function of the fetal and neonatal cardiovascular and metabolic systems. Stress was broadly defined to include environmental factors, hypoxia, maternal over-nutrition and malnutrition, physical factors including shear stress or pressure-induced forces. Particularly interesting was the concept of how NO synthesis, and its products (peroxynitrate, nitrosylated tyrosine residues) and growth factors are profoundly affected by in utero stress. We discussed the concept of developmental ‘windows’ in time, at which these stressor influences produce greater or lesser effects at certain stages of development and pregnancy. A second major and sequentially related theme was the ‘Developmental Origins of Adult Disease’, appropriately introduced by the originator of this concept, Professor David Barker (Barker 1995, 1998, 2000). Discussions focused on the concept that in utero stress ‘predisposes’ the individual to develop cardiovascular and metabolic diseases as an adult (Armitage et al. 2005; Hanson & Gluckman, 2005; McMillen et al. 2005). For example, the offspring of mothers that were nutritionally compromised in utero develop an earlier onset of cardiovascular disease (as evidenced by high blood pressure and cardiac mortality indices), as well as Type 2 diabetes and increased adiposity. These risk factors have been identified in small for gestational age babies, although it now appears that subtle developmental disturbances, rather than birth weight per se, are the major effectors of these critical developmental abnormalities (Barker, 1995, 1998). There was also lively discussion regarding the concept of ‘Predictive Adaptive Responses’, an extension of the ‘Thrifty Phenotype’ hypothesis. The theory suggests that the developing fetus can, through signals from the maternal ‘milieu’, anticipate its future environment and make necessary adaptation for survival in that environment whether rich or poor, but that if the actual environment is outside the limits of expectation, then the predictive adaptive responses can be positively disadvantageous, and disease may ensue (Armitage et al. 2005; Wallace et al. 2005; Hanson & Gluckman, 2005). The articles in this themed issue of The Journal of Physiology provide reviews and original papers which reflect the themes highlighted in the meeting and provide insight into the cardiovascular adaptation to pregnancy, and its consequences for the offspring, both short and long term, or perturbation of the maternal and fetal environment (Davis et al. 2005; Reynolds et al. 2005; Wallace et al. 2005). Notably we have included topical reviews and original research papers demonstrating the effects of distinct perturbations during gestation (nutritional restriction, energy rich exposure, preconception nutrition, fetal anaemia, hypoxia, high altitude and even cocaine exposure) and the utility of various animal models (e.g. rats, sheep, guinea pigs, etc.) on developmental programming (Armitage et al. 2005; McMillen et al. 2005; Reynolds et al. 2005; Wallace et al. 2005). Also included are articles on normal developmental changes related to cardiovascular development, placental angiogenesis (via VEGF, bFGF, etc.), nitric oxide regulation via alterations in steroid hormone receptors (e.g. oestrogen) and the renin–angiotensin system (Reynolds et al. 2005; Zheng et al. 2005). The 7 reviews and 11 research papers reflect the diversity of the research endeavours from numerous labs in what we believe will spawn new and exciting directions. The participants of this meeting and the authors of the articles hope that the questions and discussions in this themed issue of The Journal of Physiology will serve as a model, not only to those who are attempting to unravel developmental regulation of the perinatal cardiovascular and endocrine systems, but to scientists who wish to understand mechanistically how environmental influences can permanently affect the developing fetus and neonate, to increase the risk of later cardiovascular disease. The improved understanding of the basic developmental physiology of the cardiovascular system and the clinical implications that arise from this themed issue also should further justify this important multidisciplinary work.