Potential mechanisms underlying prenatal programming of hypertension in adult life were investigated using a rat model in which maternal protein intake was restricted to 9% vs. 18% casein (control) during pregnancy. Maternal low protein (MLP) offspring exhibit glucocorticoid-dependent raised systolic blood pressure throughout life (20-30 mm Hg above the control). To determine the molecular mechanisms underlying the role of alterations in glucocorticoid hormone action in the prenatal programming of hypertension in MLP offspring, tissues were analyzed for expression of the glucocorticoid receptor (GR), mineralocorticoid receptor (MR), 11betaHSD1, 11betaHSD2, and corticosteroid-responsive Na/K-adenosine triphosphatase alpha1 and beta1. GR protein (95 kDa) and messenger RNA (mRNA) expression in kidney, liver, lung, and brain was more than 2-fold greater in MLP vs. control offspring during fetal and neonatal life and was more than 3-fold higher during subsequent juvenile and adult life (P < 0.01). This was associated with increased levels of Na/K-adenosine triphosphatase alpha1- and beta1-subunit mRNA expression. Levels of MR gene expression remained unchanged. Exposure to the MLP diet also resulted in markedly reduced levels of 11betaHSD2 expression in the MLP placenta on days 14 and 20 of gestation (P < 0.001), underpinning similar effects on 11betaHSD2 enzyme activity that we reported previously. Levels were also markedly reduced in the kidney and adrenal of MLP offspring during fetal and postnatal life (P < 0.001). This programmed decline in 11betaHSD2 probably contributes to marked increases in glucocorticoid hormone action in these tissues and potentiates both GR- and MR-mediated induction of raised blood pressure. In contrast, levels of 11betaHSD1 mRNA expression in offspring central and peripheral tissues remained unchanged. In conclusion, we have demonstrated that mild protein restriction during pregnancy programs tissue-specific increases in glucocorticoid hormone action that are mediated by persistently elevated expression of GR and decreased expression of 11betaHSD2 during adult life. As glucocorticoids are potent regulators not only of fetal growth but also of blood pressure, our data suggest important potential molecular mechanisms contributing to the prenatal programming of hypertension by maternal undernutrition in the rat.
The purpose of this review is to consider how current animal models of fetal programming contribute to knowledge of the metabolic syndrome in adult humans. Low birth weight infants have an increased risk of developing cardiovascular and coronary heart disease, hypertension, diabetes and stroke in adulthood. A number of animal studies confirm the association between events during fetal life and subsequent adult disease. This review considers how these have contributed to our understanding of this relationship, and how they may help to uncover the underlying mechanisms. The importance of dietary, pharmacological, genetic and surgical models is assessed, and their usefulness in the prevention of human disease evaluated. Although progress has been made, further investigations using animals are needed to clarify the mechanisms involved in the programming of adult disease. Once these processes are understood, it may be possible to identify and protect at-risk individuals.
Potential mechanisms underlying prenatal programming of hypertension in adult life were investigated using a rat model in which maternal protein intake was restricted to 9% vs. 18% casein (control) during pregnancy. Maternal low protein (MLP) offspring exhibit glucocorticoid-dependent raised systolic blood pressure throughout life (20-30 mm Hg above the control). To determine the molecular mechanisms underlying the role of alterations in glucocorticoid hormone action in the prenatal programming of hypertension in MLP offspring, tissues were analyzed for expression of the glucocorticoid receptor (GR), mineralocorticoid receptor (MR), 11betaHSD1, 11betaHSD2, and corticosteroid-responsive Na/K-adenosine triphosphatase alpha1 and beta1. GR protein (95 kDa) and messenger RNA (mRNA) expression in kidney, liver, lung, and brain was more than 2-fold greater in MLP vs. control offspring during fetal and neonatal life and was more than 3-fold higher during subsequent juvenile and adult life (P < 0.01). This was associated with increased levels of Na/K-adenosine triphosphatase alpha1- and beta1-subunit mRNA expression. Levels of MR gene expression remained unchanged. Exposure to the MLP diet also resulted in markedly reduced levels of 11betaHSD2 expression in the MLP placenta on days 14 and 20 of gestation (P < 0.001), underpinning similar effects on 11betaHSD2 enzyme activity that we reported previously. Levels were also markedly reduced in the kidney and adrenal of MLP offspring during fetal and postnatal life (P < 0.001). This programmed decline in 11betaHSD2 probably contributes to marked increases in glucocorticoid hormone action in these tissues and potentiates both GR- and MR-mediated induction of raised blood pressure. In contrast, levels of 11betaHSD1 mRNA expression in offspring central and peripheral tissues remained unchanged. In conclusion, we have demonstrated that mild protein restriction during pregnancy programs tissue-specific increases in glucocorticoid hormone action that are mediated by persistently elevated expression of GR and decreased expression of 11betaHSD2 during adult life. As glucocorticoids are potent regulators not only of fetal growth but also of blood pressure, our data suggest important potential molecular mechanisms contributing to the prenatal programming of hypertension by maternal undernutrition in the rat.
The perinatal environment is a powerful determinant of risk for developing disease in later life. Here, we have shown that maternal undernutrition causes dramatic changes in heart structure and hypothalamo-pituitary-adrenal (HPA) function across two generations. Pregnant guinea pigs were fed 70% of normal intake from gestational days 1-35 (early restriction; ER), or 36-70 (late restriction; LR). Female offspring (F 1 ) were mated and fed ad libitum to create second generation (F 2 ) offspring. Heart morphology, blood pressure, baroreceptor and HPA function were assessed in male F 1 and F 2 offspring. ER F1 males exhibited elevated blood pressure, increased left ventricular (LV) wall thickness and LV mass. These LV effects were maintained in the ER F2 offspring. Maternal undernutrition increased basal cortisol and altered HPA responsiveness to challenge in both generations; effects were greatest in LR groups. In conclusion, moderate maternal undernutrition profoundly modifies heart structure and HPA function in adult male offspring for two generations.
The relative paucity of techniques currently available to repair bone tissue necessitates the development of innovative and more effective clinical strategies. [1,2] Of these, the combined integration of macroporous scaffolds, primed human-cell populations, and growth factors to organize and promote tissue formation is a particularly attractive approach. [3,4] However, bone tissue engineering is currently compromised by its inability to produce load-bearing scaffolds. For example, collagen scaffolds are used for a range of osteogenic applications, [5][6][7] but exhibit a compressive strength of ca. 0.034 MPa, [8] approximately three orders of magnitude lower than that of cancellous bone with values between 10 and 50 MPa. On the other hand, pure calcium phosphate mineral-based scaffolds, which currently dominate the commercial bone substitute materials market, lack a fibrillar protein component and are correspondingly brittle, typically failing catastrophically at compressive loads of less than 5 MPa.Recent studies have explored the possibility of replacing collagen with silk-based resorbable implants. [9][10][11][12] Silk is a fibrillar protein with excellent biocompatibility and mechanical strength, [13] and methodologies exist to convert silk fibers into regenerated silk fibroin solutions that can be subsequently reconstituted into macroporous 3D architectures with b-sheet secondary structure by salt leaching, gas foaming, extrusion layering or freeze drying. [9,[13][14][15][16][17][18] Although these scaffolds are potentially suitable for tissue engineering, similarly to collagenbased biomaterials the reconstituted silks are compromised by low mechanical strength, due in part to partial degradation of the native protein structure during fibroin dissolution. Moreover, attempts to impart significant mechanical reinforcement by calcium phosphate mineralization have not been very successful, due to poor adhesion and integration at the protein/mineral interface. [19,20] As a consequence, more advanced uses of silk are currently focused on novel delivery devices for morphogens, cytokines, and cell populations in models of bone defects. [21][22][23][24][25] In contrast, we present herein the first example of a silk/calcium phosphate macroporous scaffold that is load-bearing with mechanical properties comparable to cancellous bone. The mechanical strength is far in excess of other materials previously produced, and is achieved through the use of high-quality silk fibroins [26] and an integrated procedure for gelation, freezing, and mineralization. Moreover, we demonstrate the effectiveness of these load-bearing materials as nonpyrogenic osteoregenerative scaffolds by in vitro and in vivo testing, and suggest that such materials represent a new class of potentially implantable alternatives to the use of allograft and autograft procedures, for example in surgical applications, where immediate load bearing is required.Silk/calcium phosphate macroporous scaffolds were prepared by freezing phosphate-containing aqueous gels...
Epidemiological studies have led to the hypothesis that a major component of the risk of diseases such as hypertension, coronary heart disease and non-insulin-dependent diabetes (the 'metabolic syndrome') is established before birth. Although the underlying mechanisms of this 'programming' of disease have not yet been conclusively determined, a reduced fetal nutrient supply as a consequence of poor placental function or unbalanced maternal nutrition is strongly implicated. It has been proposed that one outcome of suboptimal nutrition is exposure of the fetus to excess glucocorticoids, which restrict fetal growth and programme permanent alterations in its cardiovascular, endocrine and metabolic systems. This review focuses on the effects of endogenous and exogenous glucocorticoid exposure in utero on postnatal hypothalamo-pituitary-adrenal (HPA) axis activity, both in humans and experimental animals. The physiological consequences and proposed underlying molecular and cellular mechanisms are discussed. Current data indicate that key targets for programming may include not only the HPA axis but also glucocorticoid receptor gene and 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2) gene expression in a range of tissues.
It is widely accepted that the likelihood of offspring developing heart disease, stroke, or diabetes in later life, is infl uenced by the their in utero environment and maternal nutrition. There is increasing epidemiological evidence that osteoporosis in the offspring may also be infl uenced by the mother's nutrition during pregnancy. This review provides evidence from a range of animal models that supports the epidemiological data; suggesting that lifelong bone development and growth in offspring is determined during gestation.
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