Original Article

05/10/2004
The foetal and perinatal programming of cardio-vascular and metabolic diseases in the adult

Prof. Umberto Simeoni
Assistance Publique Hôpitaux de Marseille - Hôpital d’enfants de la Timone (France)

Epidemiologic studies on several large cohorts of adults whose anthropometric characteristics at birth were known have shown that coronary heart disease incidence and mortality increase with decreased birth weight. Concomitantly, increased risk for arterial hypertension and insulin-resistance has been reported. Postnatal overnutrition following intra-uterine growth restriction (IUGR) may play an additional role in the late development of obesity and type 2 diabetes [1], while rapid postnatal catch-up growth may be a principal factor associated with cardio-vascular mortality. Such findings in humans have been reproduced with various animal models of IUGR, in particular in the rat, which adds further evidence to the theory that a programming mechanism triggered by fetal stress may lead to cardio-vascular and metabolic consequences in the adult. Dietary restrictions during pregnancy in the rat, including protein restriction [2] and iron restriction [3] to the dam, induce increased arterial blood pressure in the offspring. Arterial hypertension appears to be prolonged in such rats and their life span has been shown to be shorter in some studies [4,5]. The cost of fetal adaptation to intra-uterine stress conditions may thus affect adult life by increasing the risk for cardio-vascular and metabolic diseases. Low birth weight is now recognized as a significant risk factor for cardiovascular disease, alongside with hypercholesterolemia, arterial hypertension, obesity, diabetes, tobacco exposure or insufficient physical activity. However, the detailed mechanisms of such programming are still incompletely known. Possibly multi-factorial, such pathogenesis may involve in particular renal and vascular mechanisms on the one side, and endocrine factors on the other.

Renal and vascular mechanisms of fetal programming

Nephron number reduction

Nephrogenesis is achieved in humans around 34-36 weeks of gestation, and leads to the development of approximately a cumulative number of 1 to 1.2 million nephrons in both kidneys. The total number of nephrons contained in the kidneys thus constitutes a capital that is definitive once nephrogenesis has been achieved, and conditions the functional renal capacity of each individual. In some widely studied animal species, such as rat or rabbit, the end of nephrogenesis occurs after birth, allowing extended studies on the consequences of its alteration.
Although it has been shown that the number of nephrons is variable to some extent among normal individuals, according to probably to both genetic and environmental factors, it is clearly established that intra-uterine growth restriction alters nephron formation and induces a definitively reduced total number of nephrons .
Indeed, a reduced size of kidneys is observable on antenatal ultrasounds in humans in conditions of IUGR [6]. Studies on necropsies of human fetuses have shown that the total number of nephrons is proportional to birth weight [7], and an approximately 35% nephron number deficit has been found in infants whose birth weight is lower than the 3rd centile [8].
Various animal studies have shown that IUGR in several animal species is associated with a reduced number of nephrons [9,10]. IUGR in offspring can be achieved in animal models of maternal diet protein deprivation (i.e. 9% instead of 18% protein caloric intake throughout the period of nephrogenesis), corticosteroids injection during pregnancy, or uterine artery ligation. In such experimental models, kidney size is reduced, as well as the total number of nephrons, parallel to birth weight [11]. Obviously, such an alteration is permanent and is not influenced by postnatal nutrition. To the contrary, postnatal nutrition seems to induce catch-up growth while the total number of nephrons is diminished.
Similarity of effects obtained under different experimental conditions suggests a common pathway for nephron mass reduction, although it is still incompletely understood. Renal blood flow reduction during foetal life may constitute a key factor, due to a distributive alteration of oxygen delivery that sacrifices the kidney in conditions of foetal stress.
Retinol, and its derivative, retinoic acid act through the stimulation of nuclear receptors and control expression of a number of genes involved in development, have been shown to be principal factors in the determination of the definite number of nephrons. Mechanisms of the effects of maternal nutritional deficiency on the foetal kidney are better known from metanephric culture models. Retinol is involved in the induction of the epithelial transformation of undifferenciated mesenchyme cells in the metanephros, by the ureteric bud. C-ret proto-oncogen expression is altered by vitamin A deficiency. Other growth factors involved in the inductive process of renal epithelial transformation, such as the Glial cell line-derived neurotrophic factor (GDNF) and midkine are concerned by vitamin A deficiency [12,13]. It is unclear to which extent vitamin A deficiency per se may explain the reduction in nephron number observed in circumstances of maternal diet proteins deprivation. Vitamin A supplementation to pregnant rats receiving a hypoproteinic diet prevents the reduction of nephron number in their low birth weight offspring [14]. Other environmental factors however may alter fetal renal growth and development. High dose or fluorinated corticosteroids can induce nephron mass reduction in the foetus when administered to pregnant rats or ewes, as they overwhelm the activity of placental, type 2-11-beta–hydroxysteroid dehydrogenase (11?-HSD-2), an enzyme that protects the foetus from excess maternal endogenous steroids [15]. Ciclosporin A administered to the pregnant rat can induce a diminution of nephron number as well [16].
Especially, epigenetic mechanisms may alter gene methylation, a process that is responsible for gene inactivation. De-methylation of such genes as the p53, which controls the expression of the p53 pro-apoptotic factor, has been shown to occur during IUGR induced in rats by uterine artery ligation [17]. Methyl radicals availability is related to nutrition, and methylation and de-methylation processes are influenced by oxygen free radicals, which are generated as highly reactive species during ischaemic and hypoxic injuries. Gene methylation alteration has prolonged effects and constitutes an epigenetic memory, that may per se alter durably gene function and explain partly the long lasting effects of foetal programming [18].
Independently on birth weight, it has been shown recently in a study of necropsy findings in patients with arterial hypertension who died in accidents, that nephron number was markedly reduced, compared to controls, while size of glomeruli was increased [19].

Glomerular hyperfiltration

It has been long suspected that susceptibility to acquired renal diseases, arterial hypertension, glomerulosclerosis and chronic renal insufficiency in the adult is related to the provisional number of nephrons acquired in utero [20]. Glomerular single nephron hyperfiltration is responsible for long term proteinuria, glomerulosclerosis and finally arterial hypertension. Considering the consequences of nephron deficiency in general, it is interesting to notice that the age at which the nephron mass reduction occurs determines the importance of long term effects. Nephron deficiency that occurs in the adut, for example due to unilateral nephrectomy, does not seem to cause significant, long term sequels. To the contrary, when nephron mass reduction occurs early in life, arterial hypertension may be observed in the adult [21].

Renin angiotensin system and other vascular factors

Maternal nutritional deficiency during gestation in rats causes marked nephron number reduction considerably decreases expression of the intarrenal components of the renin-angiotensin system (RAS) in the fetal and neonatal kidney. Woods et al showed that maternal diet protein restriction deeply decreases renin mRNA, and renal angiotensin and renin expression in the neonatal offspring, followed by reduced glomerular filtration rate and increased mean arterial pressure [22]. Several components of the RAS are known to be important growth factors of the fetal kidney. Indeed, pharmacological suppression of the RAS during gestation is associated with nephron number reduction and arterial hypertension in the adult [23]. Moreover, utero-placental insufficiency in the sheep, a model that causes altered foetal nutrition, is also accompanied by an extinction of the foetal intra-renal RAS [24]. It is however still unclear whether the extinction of the renal RAS components during foetal life is a cause, or a consequence of the nephron number reduction.
To the contrary, in the young and the adult rat, upregulation of the RAS appears to be responsible for arterial hypertension in protein deprived offspring. In such experimental model, the increase in arterial blood pressure is prevented by early administration of the angiotensin-converting enzyme inhibitor captopril [25], as well as the AT1 subtype, angiotensin II receptor blocker losartan, but is not influenced by the calcium entry blocker nifedipine [26]. Moreover, Sahajpal and Ashton have recently shown that, in young rats exposed to intrauterine protein deprivation, compared to control rats, both the response to non-pressor doses of angiotensin II, measured as a reduction of glomerular filtration rate, and AT1 angiotensin II receptor subtype expression in the whole kidney, are increased [27]. Taken together, such data suggests that both expression of and responsiveness to the RAS are upregulated during early adulthood in such experimental models.
It can be noted that the RAS is involved in the development of arterial hypertension in spontaneously hypertensive rats (SHR). In such model, arterial hypertension follows the installation in the young rat of decreased glomerular filtration rate and salt retention [28]. Increased responsiveness to angiotensin II has been observed in young, genetically hypertensive rats [29,30], whose hypertension is moreover responsive to ACE inhibition or AT1 angiotensin II receptors bloking on the long term [31,32].
Aside the RAS, other systems of regulation may be altered in conditions of fœtal stress, such as the renal prostaglandins, the L-arginin/nitric oxide pathway components, as many factors controlling renal vascular tone are involved as growth factors involved in renal development.

Effects of postnatal overfeeding

Optimal nutrition to be provided postnatally to low birth weight infants with intra-uterine growth retardation is still a matter of debate. Current practice tends to privilege catch-up growth with early, high proteic and caloric intakes. Short and long term effects of such approach are under investigation as nutritional and growth benefits may be balanced by consequences on renal glomerular function and enhanced effects of “fetal programming”. Increased protein load is known to induce glomerular hyperfiltration. In rat, overfeeding during the postnatal period by reducing the number of pups in litters induces metabolic alterations that are similar to the syndrome “X” in adults [33]. Studies on such experimental model have underlined hypothalamic pituitary adrenal axis hyperactivity [34].
The long term effects of the association of fetal undernutrition and postnatal overfeeding are suggested by studies in humans [35] and in rats, including: arterial hypertension, hyperinsulinism, hyperleptinemia, increased body fat, hyperphagia and decreased kidney weight [36].

Role of glucosteroids

Corticosteroids are a likely common path to trigger cardio-vascular and metabolic effects of foetal programming. Generally proposed mechanisms include increased placental transfer of maternal glucocorticoids, despite placental 11?-HSD-2 [37], and increased sensitivity of the hypothalamo-pituitary-adrenal axis. Steroids exert marked effects on antenatal and postnatal renal function (reviewed in [38]). Administration of glucocorticoids during gestation in various mammal species is known to cause a reduction of birth weight. Prenatal dexamethasone has been shown to induce a nephron number reduction [15]. Experimental inhibition of placental 11?-HSD-2, as it increases intra-uterine exposure to endogenous steroids, produces similar effects [39]. 11?-HSD-2 activity correlates to birth weight and inversely correlates to the placental mass [40]. Its activity is decreased in conditions of maternal low protein diet [41]. Furthermore, the effect of corticosteroids may be mediated by a decreased activity of tissue 11?-HSD-2, and a prolonged, increased expression of glucocorticoid receptors [42].
It has been shown in the foetal lamb that antenatal cortisol infusion, either at “parturient” doses on day 130 [43] or at high doses on days 109-116 [44] down-regulates the expression of rennin mRNA.
As common conditions leading to IUGR are characterized by foetal stress and tend to stimulate corticosteroid production both in the mother and the foetus, and as corticosteroids are known to induce arterial hypertension and carbohydrates metabolism alterations, the hypothesis of a central role of corticoids in the pathogenesis of fetal programming has gained substance. A prolonged, durable alteration of the response to stress, characterized with increased cortisol concentrations and enhanced expression of glucocorticoid receptors has been proposed as an explanation for arterial hypertension that is observed in adulthood of such patients. In particular, it has been shown that maternal protein deprivation during pregnancy in rats is responsible for an alteration of the foetal hypothalamic pituitary adrenal axis, both in basal and in stress conditions [45]. Finally, antenatal exposure to corticosteroids in rats can induce hyperglycaemia in the offspring [46]. More generally, corticosteroids tend to accelerate the maturation of cellular functions and metabolic equipment. Accelerated maturation allows a transiently improved function but may lead to permanent structural alterations that may be considered as the “cost’ for the preservation of the foetus in adverse environmental conditions.

Vascular mechanisms

Aside renal mechanisms, fetal programming of cardio-vascular and metabolic diseases may involve direct, vascular structural of functional alterations acquired during the prenatal or early postnatal period. The anatomical development of vasculature is characterized with specific needs and a precise timing, whose alteration may lead to definite dysfunction, and favour the later development of arterial hypertension. Altered distribution of capillaries in the kidneys of growth restricted animals has been reported. Resistance arteries wall remodelling may be involved in vascular dysfunction and late arterial hypertension. Accumulation of elastic factors within the wall of arteries during foetal ,development is a timed process whose alteration may induce definitive vascular dysfunction []. For example elastin is principally accumulated within the wall of arteries during the foetal period, while no or poor synthesis is considered to occur after birth. Given that the half-life of elastin is several decades, elastin deficient arteries due to IUGR or preterm birth may display inappropriate compliance and visco-elastic properties that may favour later hypertension.
However, arterial hypertension in the adult is not obtained in all experimental models, albeit vascular dysfunction may be evidenced, suggesting in particular that the timing of the occurrence of foetal stress is crucial [48].

The expression and the effects of factors controlling arterial development and arterial tone, such as the RAS, may as well be disturbed in conditions of foetal stress. Renal vascular arterial responses to angiotensin II and nitric oxide (NO) are developmentally specific [49] and may be altered by changing conditions of intrauterine environment. So is the switch between the predominance of the AT2 subtype to the AT1 subtype of angiotensin II receptors, that characterizes the transition from the foetal to the mature condition [50]. Finally, preliminary data suggest that NO-dependent cerebral vascular reactivity in rat pups is altered after maternal diet protein deprivation, by an original mechanism of regulation that involves prostaglandin E2 [51].

There is thus increasing evidence, both from epidemiological studies and from experiments that elucidate mechanisms, that cardiovascular and metabolic diseases in the adult may result at least partially from programming in utero and during the early postnatal period.

References

1. Barker DJP, Osmond C, Golding J, Kuh D, Wadsworth MEJ. Growth in utero, blood pressure in childhood and adult life, and mortality from cardio-vascular disease. BMJ 1989; 298:564-567 (PubMed).
2. Langley SC, Jackson AA. Increased systolic blood pressure in adult rats induced by foetal exposure to maternal low protein diet. Clin Sci 1994; 86:217-222 (PubMed).
3. Lewis RM, Forhead AJ, Petry CJ, Ozanne SE, Hales CN. Long-term programming of blood pressure by maternal diet iron restriction in the rat. Br J Nutr 2002; 88:283-290 (PubMed).
4. Vehaskari VM, Aviles DH, Manning J. Prenatal programming of adult hypertension in the rat. Kidney Int 2001; 59:238-245 (PubMed).
5. Aihie Sayer A, Dunn R, Langley-Evans S, Cooper C. Prenatal exposure to a maternal low protein diet shortens life span in rats. Gerontology 2001; 47:9-14 (PubMed).
6. Konje JC, Bell SC, Morotn JJ, Dechazl R, Taylor DJ. Human fetal kidney morphometry during gestation and the relationship between weight, kidney morphometry and plasma active renin concentration at birth. Clin Sci 1996; 91:169-175 (PubMed).
7. Vilar J, Merlet-Bénichou C. Oligonéphronie congénitale et pression artérielle de l’adulte. In : Simeoni U., Gouyon J-B, Guignard JP. Hémodynamique, pression artérielle et rein chez le nouveau-né. Elsevier, Paris, 2000 ; pp24-32.
8. Hinchliffe S, Lynch M, Sargent P, Howard C, Van Velzen D. The effect of intrauterine growth retardation on the development of renal nephrons. Br J Obstet Gynaecol 1992; 99:296-301 (PubMed).
9. Langley-Evans SC, Welham SJM, Jackson AA. Fetal exposure to maternal low protein diet impairs nephrogenesis and promotes hypertension in the rat. Life Sci 1999; 64:965-974 (PubMed).
10. Zeman FJ. Effects of maternal protein restricition on the kidney of the newborn young of rats. J Nutr 1968; 94:111-116.
11. Merlet-Bénichou C, Gilbert T, Muffat-Joly M, Lelièvre-Pégorier M, Leroy B. Intrauterine growth retardation leads to a permanent nephron deficit in the rat. Pediatr Nephrol 1994; 8:175-180 (PubMed).
12. Moreau E, Vilar J, Lelièvre-Pégorier M, Merlet-Bénichou C, Gilbert T. Regulation of c-ret expression by retinoic acid in rat metanephros: implication in nephron mass control. Am J Physiol 1998; 275:F938-F945 (Full Text).
13. Vilar J, Lalou C, Duong Van Huyen JP, Charrin S, Hardouin S, Raulais D, Merlet-Bénichou C, Lelièvre-Pégorier M. Midkine is involved in kidney development and in its regulation by retinoids. J Am Soc Nephrol 2002; 13:668-676 (PubMed).
14. Lelièvre-Pégorier M, Vilar J, Freund N, Gilbert T, Merlet-Bénichou C. Vitamin A prevents nephron deficit in growth-retarded fetal rats. J Am Soc Nephrol 1998; 9:501.
15. Celsi G, Kistner A, Eklöf A, Ceccatelli S, Aizman R, Jacobson S. Inhibition of renal growth by prenatal dexmethasone and the programming of blood pressure in the offspring. J Am Soc Nephrol 1997; 8:296.
16. Gilbert T, Gaonach S, Moreau E, Merlet-Bénichou C. Effect of ciclosporine A on rat metanephros differentiation in vitro. J Am Soc Nephrol 1994; 5:623.
17. Pham T.D., MacLennan N.K., Chiu C.T., Laksana G.S., Hsu J.L. and Lane R.H. Uteroplacenta insufficiency increases apoptosis and alters p53 gene methylation in the full-term IUGR rat Kidney. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2003; 285: R962-R970 (PubMed).
18. Waterland R. and Garza C. Potential mechanisms of metabolic imprinting that lead to chronic disease. Am. J. Clin. Nutr. 1999; 69:179-97 (Full Text).
19. Keller G, Zimmer G, Mall G, Ritz E, Amann K. Nephron number in patients with primary hypertension. N Engl J Med 2003; 348:101-8 (PubMed).
20. Brenner BM, Garcia DL, Anderson S. Glomeruli and blood pressure. Less of one more of the other? Am J Hypertens 1988;1:335-347 (PubMed).
21. Woods LL. Neonatal uninephrectomy causes hypertension in adult rats. Am J Physiol 1999; 276:R974-R978 (Full Text).
22. Woods LL, Ingelfinger JR, Nyengaard JR, Rasch R. Maternal protein restriction suppesses the newborn renin-angiotensin system and programs adult hypertension in rats. Pediatr Res 2001; 49:460-467 (Full Text).
23. Woods LL, Rasch R. Perinatal angiotensin II programs adult blood pressure, glomerular number, and renal function in rats. Am J Physiol 1998; 275:R1593-R1599 (PubMed).
24. Zhang DY, Lumbers ER, Simonetta G, Wu JJ, Owens JA, Robinson JS, McMillen IC. Effects of placental insuficiency on the ovine fetal renin-angiotensin system. Exp Physiol 2000; 85:79-84 (PubMed).
25. Sherman RC, Langley Evans SC. Early administration of angiotensin-converting enzyme inhibito captopril prevents the development of hypertension programmed by intrauterine exposure to a maternal low-protein diet in the rat. Clin Sci 1998; 94:373-81 (PubMed).
26. Sherman RC, Langley Evans SC. Antihypertensive treatment in early postnatal life modulates prenatal dietary influences upon blood pressure in the rat. Clin Sci 2000; 98:269-75 (PubMed).
27. Sahajpal V, Ashton N. Renal function and angiotensin II receptor expression in young rats following intrauterine exposure to a maternal low-protein diet. Clin Sci 2003; 104:607-614 (PubMed).
28. Beierwaltes WH, Arendhorst WJ, Klemmer PJ. Electrolyte and water balance in young spontaneously hypertensive rats. Hypertension 1982; 4:908-15 (PubMed).
29. Vyas SJ, Jackson EK. Angiotensin II enhanced renal responsiveness in young genetically hypertensive rats. J Pharmacol Exp Ther 1995;273:768-77 (PubMed).
30. Gouldsborough I, Ashton N. Maternal environment alters renal response to angiotensin II in the spontaneously hypertensive rat. Clin Exp Pharmacol Physiol 2001 ; 28:504-9 (PubMed).
31. Harrap SB, Van der Merwe WM, Griffin SA, MacPherson F, Lever AF. Brief angiotensin converting enzyme inhibitor treatment in young spontaneously hypertensive rats reduces blood pressure long-term. Hypertension 1990;16:603-14 (PubMed).
32. Morton JJ, Beattie EC, MacPherson F. Angiotensin II receptor antagonist losartan has persistant effects on blood pressure in the young spontaneously hypertensive rat: lack of relation to vascular structure. J Vasc Res 1992;29:264-9 (PubMed).
33. Plagemann A, Harder T, Rake A, Voits M, Fink H, Rohde W, Dörner G. Perinatal elevation of hypothalamic insulin, acquired malformation of hypothalamic galaninergic neurons and syndrome x-like alterations in adulthood of neonatally overfed rats. Brain Research 1999; 836:146-155 (PubMed).
34. Boullu-Ciocca S, Paulmyer-Lacroix O, Oliver C, Guillaume V, Grino M; Postnatal overfeeding induces obesity and permanently programs insulin sensitivity at the adulthood. Eur J Physiol, in press (abstract).
35. Eriksson JG, Forsen T, Tuomilheto J, Winter PD, Osmond C, Barker DJP. Catch-up growth in childhood and death from coronary heart disease: longitudinal study. Brit Med J 1999; 318:427-31 (Full Text).
36. Vickers MH, Breier BH, Cutfield WS, Hofman PL, Gluckman PD. Fetal origins of hyperphagia, obesity and hypertension and postnatal amplification by hypercaloric nutrition. Am J Physiol Endocrinol Metab 2000; 279:E83-E87 (Full Text).
37. Edwards C.R.W., Benediktsson R., Linsay R.S and Seckl J.R. Dysfunction of placenta glucocorticoid barrier: link between fetal environment and adult hypertension. Lancet 1993; 341: 355-357.
38. Cattarelli D, Matis J, Simeoni U. Effets rénaux des corticoïdes administré en période anténatale ou postnatale. In : Guignrd J-P, Gouyon J-B, Simeoni U. Médicaments. Néphrotoxicité. Insuffisance rénale aiguë chez le nouveau-né. Elsevier, Paris, 2001, pp30-35.
39. Seckl JR. Glucocorticoid programming of the fetus; adult phenotypes and molecular mechanisms. Molec Cell Endocrinol 2001; 185:61-71 (PubMed).
40. Benediktsson R, Lindsay RS, Noble J, Seckl JR, Edwards CR. Glucocorticoid exposure in utero: new model for adult hypertension. Lancet. 1993 ;341:339-41 (PubMed).
41. Langley-Evans SC, Philips GJ, Benediktsson R, Gardner DS, Edwards CRW, Jackson AA, Seckl JR. Protein intake in pregnancy, placental glucocorticoid metabolism and the programming of hypertension in the rat. Placenta 1996; 17:169-172 (PubMed).
42. Bertram C, Trowern AR, Copin N, Jackson AA, Whorwood CB. The maternal diet during pregnancy programs altered expression of the glucocorticoid receptor and type 2 11beta hydroxy steroid dehydrogenase: potential molecular mechanisms underlying the programming of hypertension in utero. Endocrinology 2001; 142:2841-2853 (Full Text).
43. Segar JL, Bedell K, Page Wv, Mazursky JE, Nuyt A-M, Robillard JE. Effect of cortisol on gene expression of the renin-angiotensin system in fetal sheep. Pediatr Res 1995; 37:741-746 (PubMed).
44. Williams SJ, Olson DM, Zaragoza DB, Couletr CL, Butler TG, Ross JT, McMillen IC. Cortisol infusion decreases rennin, but not PGHS-2, EP2, or EP4 mRNA expression in the kidney of the fetal sheep at days 109-116. Pediatr Res 2004; 55:637-44 (PubMed).
45. Leonhardt M, Lesage J, Dufourny L, Dickez-Coopman A, Montel V, Dupouy JP. Perinatal maternal food restriction induces alterations in hypothalamo-pituitary-adrenal axis activity and in plasma corticosterone-binding globulin capacity of weaning rat pups. Neuroendocrinology 2002; 75:45-54 (PubMed).
46. Nyirenda MJ, Welberg LAM, Seckl JR. Programming hyperglycemia in the rat through prenatal exposure to glucosteroids - fetal effect or maternal influence? J Endocrinol 2001; 170:653-660 (PubMed).
47. Martyn CN, Greenwald SE. Impaired synthesis of elastin in walls of aorta and large conduit arteries during early development as an initiating event in pathogenesis of systemic hypertension. Lancet. 1997;350:953-5 (PubMed).
48. Holemans K, Gerber R, Meurrens K, De Clerck F, Poston L, Van Assxhe FA. Maternal food restriction in the second half of pregnancy affects vascular function but not blood pressure of rat female offspring. Br J Nutr 1999; 81:73-79 (PubMed).
49. Simeoni U, Zhu B, Judes C, Massfelder T, Geisert J, Helwig J-J. Postnatal Development of Vascular Resistance of the Rabbit Isolated Perfused Kidney: Modulation by Nitric Oxide and Angiotensin II. Pediatr Res, 1997, 42:550-555 (PubMed).
50. Velaphi SC, Roy T, Despain K, Rosenfeld CR. Differential responses to systemic and local angiotensin II infusions in conscious fetal sheep. Pediatr Res 2002; 52:333-41 (PubMed).
51. Gobeil F Jr, Dumont I, Marrache A, Vazquez-Tello, Bernier SG, Abran D et al. Regulation of eNOS expression in brain endothelial cells by perinuclear EP(3) receptors. Circ Res 2002; 90:682-9 (PubMed).

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