Fetal Programming Of Hypertension Research Articles

The Role of DNMT and HDACs in the Fetal Programming of Hypertension by Glucocorticoids.

The causes of hypertension are complex and involve both genetic and environmental factors. Environment changes during fetal development have been linked to adult diseases including hypertension. Studies show that timed in utero exposure to the synthetic glucocorticoid (GC) dexamethasone (Dex) results in the development of hypertension in adult rats. Evidence suggests that in utero stress can alter patterns of gene expression, possibly a result of alterations in the topology of the genome by epigenetic markers such as DNA methyltransferases (DNMTs) and histone deacetylases (HDACs). The objective of this study was to determine the effects of epigenetic regulators in the fetal programming and the development of adult hypertension. Specifically, this research examined the effects of the HDAC inhibitor valproic acid (VPA) and the DNMT inhibitor 5-aza-2′-deoxycytidine (5aza2DC) on blood pressure (BP) and gene expression in prenatal Dex-programmed rats. Data suggest that both VPA and 5aza2DC attenuated the Dex-mediated development of hypertension and restored BP to control levels. Epigenetic DNMT inhibition (DNMTi) or HDAC inhibition (HDACi) also successfully attenuated elevations in the majority of altered catecholamine (CA) enzyme expression, phenylethanolamine N-methyltransferase (PNMT) protein, and elevated epinephrine (Epi) levels in males. Although females responded to HDACi similar to males, DNMTi drove increased glucocorticoid receptor (GR) and PNMT expression and elevations in circulating Epi in females despite showing normotensive BP.

Fetal programming of adrenal PNMT and hypertension by glucocorticoids in WKY rats is dose and sex-dependent.

Biochemical changes in utero may alter normal fetal development, resulting in disease later in life, a phenomenon known as fetal programming. Recent epidemiological studies link fetal programming to negative health outcomes, such as low birth weight and hypertension in adulthood. Here, we used a WKY rat model and studied the molecular changes triggered by prenatal glucocorticoid (GC) exposure on the development of hypertension, and on the regulation of phenylethanolamine N-methyl transferase (PNMT), the enzyme responsible for biosynthesis of epinephrine, and a candidate gene linked to hypertension. Clinically, high doses of the synthetic GC dexamethasone (DEX) are used to treat infant respiratory distress syndrome. Elevated maternal GCs have been correlated with fetal programming of hypertension. The aim of this study was to determine if lower doses of DEX would not lead to detrimental fetal programming effects such as hypertension. Our data suggests that prenatal stress programs for increased expression of PNMT and altered regulation of PNMT in males and females. Importantly, we identified that DEX mediated programming was more apparent in the male rats, and the lower dose 10μg/kg/day of DEX did not lead to changes in blood pressure (BP) in female rats suggesting that this dose is below the threshold for programming of hypertension. Furthermore, sex-specific differences were observed in regards to programming mechanisms that may account for hypertension in males.

Vascular angiotensin AT1 receptor neuromodulation in fetal programming of hypertension

Fetal stress increases the susceptibility to cardiovascular diseases in adult age, including hypertension, a process known as fetal programming of hypertension (FPH). This study intends to investigate the interplay between vascular sympathetic nervous system (SNS) and RAS, namely the neuromodulatory role exerted by Angiotensin II (Ang II) receptor-1 (AT1) in FPH, and respective contribution for hypertension. Methods6-month old Sprague-Dawley offspring from mothers fed ad-libitum (CONTROL) or with 50% intake during the second half of gestation (maternal undernutrition, MUN) were used. Sympathetic neurotransmission was studied in mesenteric/tail arteries and mesenteric veins by electrically-evoked [3H]-noradrenaline release experiments using RAS drugs. AT1 receptors in sympathetic nerves of mesenteric arteries were investigated by immunohistochemistry and Laser Scanning Confocal Microscopy. ResultsAng II facilitated noradrenaline release in the vessels studied from MUN and CONTROL rats. Losartan induced a tonic facilitation only in MUN vessels. Sympathetic innervation was larger in MUN versus CONTROL vessels. AT1 receptors on sympathetic nerves were present in higher amounts in MUN versus CONTROL vessels. ConclusionsFindings support that FPH is associated with a vascular hyper-sympathetic activation, involving a tonic facilitation of prejunctional AT1 receptors by endogenous Ang II, which can justify, at least in part, the development of hypertension.

Sex differences in the fetal programming of hypertension: role of adrenal phenylethanolamine N‐methyltransferase gene expression (680.21)

Prenatal exposure to high levels of glucocorticoids (GCs) predisposes to hypertension in later life. GCs regulate catecholamine biosynthesis and are critical for blood pressure homeostasis. This study examined whether prenatal exposure to elevated GCs influences the development of adult hypertension via alterations in phenylethanolamine N‐methyl transferase (PNMT), a gene that is linked to hypertension. Pregnant Wistar‐Kyoto dams were injected with 100 μg/kg/day of the synthetic GC dexamethasone (DEX) in their third trimester. Blood pressure and weights of the offspring were measured from week 3‐18, at which point the animals were sacrificed. Total RNA and protein were extracted from the adrenals, and the expression of PNMT and its regulatory transcription factors analyzed by qPCR and Western blot. Results reveal that in utero exposure to DEX promotes the development of hypertension in the offspring. A more pronounced increase in blood pressure was seen in males than females. The mRNA transcripts for PNMT, and its transcriptional regulators Egr‐1, Sp1, GR and AP‐2, were elevated in the adrenals of these animals compared to saline controls, with differences in both sexes. Preliminary Western data also shows upregulation of PNMT and the transcription factor Egr‐1. These results suggest that prenatal GC exposure increases adrenal PNMT gene expression via altered transcriptional regulatory mechanisms.Grant Funding Source: Supported by CIHR

How the Kidney Is Impacted by the Perinatal Maternal Environment to Develop Hypertension1

Environmental conditions during perinatal development such as maternal undernutrition, maternal glucocorticoids, placental insufficiency, and maternal sodium overload can program changes in renal Na(+) excretion leading to hypertension. Experimental studies indicate that fetal exposure to an adverse maternal environment may reduce glomerular filtration rate by decreasing the surface area of the glomerular capillaries. Moreover, fetal responses to environmental insults during early life that contribute to the development of hypertension may include increased expression of tubular apical or basolateral membrane Na(+) transporters and increased production of renal superoxide leading to enhanced Na(+) reabsorption. This review will address the role of these potential renal mechanisms in the fetal programming of hypertension in experimental models induced by maternal undernutrition, fetal exposure to glucocorticoids, placental insufficiency, and maternal sodium overload in the rat.

Characterization of Brainstem Phenylethanolamine N‐methyltransferase Gene Expression in Fetal Programming of Hypertension

An unfavourable fetal environment results in low birth weight offsprings and the development of hypertension later in life. This concept of fetal programming proposes that elevated levels of glucocorticoids during fetal development leads to alterations in blood pressure regulatory mechanisms. Adrenaline, a neurotransmitter synthesized by the enzyme phenylethanolamine N‐methyltransferase (PNMT), is involved in the sympathetic control of blood pressure and is elevated in hypertensive patients. Dysregulation of the PNMT gene has been linked to the pathogenesis of hypertension and is therefore a candidate gene involved in fetal programming of hypertension. Results from this study show that Wistar Kyoto rats exposed to dexamethasone (DEX: 10, 50 or 100 μg/kg/day) in the third trimester, developed elevated blood pressure as adults. The elevations in arterial blood pressures correlate with the increased dose of prenatal DEX exposure. In addition, PNMT mRNA in the C1, C2 and C3 adrenergic brainstem regions were elevated in prenatally DEX exposed adult rats. Analysis of transcriptional regulators of the PNMT gene shows a dose‐dependent upregulation in the mRNA for Sp1, EGR‐1 and AP2 in the C2 and C3 regions; whereas GR mRNA was increased in the C3 region only. These results suggest that prenatal glucocorticoid exposure increases brainstem PNMT gene expression via altered transcriptional regulatory mechanisms.

Epigenetic changes in gene expression: focus on “The liver X-receptor gene promoter is hypermethylated in a mouse model of prenatal protein restriction”

the term epigenetics was first coined in 1942 by Waddington ([20][1]) to describe the interaction of genes with their environment during development that gives rise to a phenotype. Today, the term epigenetics is used when describing a phenotype that occurs in a manner outside conventional genetic

Developmental programming of sex-dependent alterations in lipid metabolism: a role for long-term, sex-specific alterations in LDL-receptor expression. Focus on “Developmental programming of lipid metabolism and aortic vascular function in C57BL/6 mice: a novel study suggesting an involvement of LDL-receptor”

the nobel prize in physiology or medicine was awarded to Brown and Goldstein in 1985 for their discovery of the low-density lipoprotein (LDL) receptor and its importance in the regulation of cholesterol metabolism ([2][1]). Cholesterol, an essential component of the mammalian cell membrane, is

Intrauterine Growth Restriction: Fetal Programming of Hypertension and Kidney Disease

The etiology of hypertension historically includes 2 components: genetics and lifestyle. However, recent epidemiologic studies report an inverse relationship between birth weight and hypertension suggesting that a suboptimal fetal environment may also contribute to increased disease in later life. Experimental studies support this observation and indicate that cardiovascular/kidney disease originates in response to fetal adaptations to adverse conditions during prenatal life.

Role of Fetal Programming in the Development of Hypertension

Epidemiological studies have suggested that size at birth contributes to increased cardiovascular disease (CVD) risk in later life. Findings from experimental studies are providing insight into the mechanisms linking impaired fetal growth and the increased risk of CVD and hypertension in adulthood. This article summarizes potential mechanisms involved in the fetal programming of hypertension and CVD, including alterations in the organs and regulatory systems critical to long-term control of sodium and volume homeostasis.

Abstract 2526: Fetal Programming of Hypertension: Decreased Compliance and IGF-I Plasma Levels in Umbilical Arteries of Infants with Intrauterine Growth Restriction

Background : Epidemiological studies link intrauterine growth restriction (IUGR) to arterial hypertension in adulthood. Intrauterine stress may induce decreased arterial compliance that persists after birth, thus predisposing the individual for arterial hypertension in adult life. Methods and Results : We compared umbilical arteries from IUGR (n=13, <5 th weight percentile) vs. appropriate for gestational age (AGA) infants (n=13) using structural and functional analyses. Vessel wall thickness and stiffness were determined in umbilical artery-derived vessel rings. Vessel wall elastin, the main determinant of arterial elasticity, was quantified by elastin extraction. Cord blood was assayed for growth factors known to modulate vessel wall matrix. IUGR infants had decreased umbilical artery compliance in vivo in terms of an increased resistance-index (P<0.05). In parallel, the vessel wall area of umbilical arteries in the IUGR group was significantly smaller than in the AGA group (2.8 vs. 3.8 mm 2 , P<0.05). Myographic measurements showed that maximal tension [mN/mm] as well as maximal force [mN] were both significantly increased in IUGR arteries compared with AGA arteries (P<0.05). Serum levels of IGF-I, a regulator of elastin synthesis, were significantly lower in IUGR cord blood (P<0.01) than in AGA cord blood. These IGF-I serum levels correlated significantly with maximum tension in umbilical arteries (P<0.01). In parallel, we found a trend to reduced elastin content in the vessel wall of IUGR vessels. Conclusions : IUGR infants possess thinner and stiffer umbilical arteries than AGA infants. Low intrauterine IGF-I serum levels may account for reduced arterial elastin at birth, thereby providing a potential link to arterial hypertension in adulthood.

Elucidating molecular mechanisms of the developmental origins hypothesis: p53 phosphorylation, apoptosis, and nephrogenesis

epidemiologic studies show that humans born small for gestational age are disposed to developing type 2 diabetes, obesity, hypertension, and cardiovascular disorders (the “metabolic syndrome”) during adulthood ([3][1], [4][2]). The mechanisms by which intrauterine growth restriction (IUGR) leads

Sex differences in a rat model of fetal programming of hypertension

Fetal programming hypothesizes that insults during fetal life result in fetal adaptations leading to adult disease. Thus, the fetal environment is considered a factor in the etiology of hypertension (HT). Our laboratory has developed a unique model of intrauterine growth restriction (IUGR) induced by reduced uterine perfusion initiated by placement of silver clips around the abdominal aorta and ovarian arteries in late gestation. This model of fetal programming of hypertension demonstrates sex differences, as only adult male IUGR offspring are hypertensive. However, the purpose of this study was to determine if testosterone (T) contributes to the hypertension in male IUGR offspring. Mean arterial pressure (MAP) and T were significantly increased in male IUGR offspring as compared to male control offspring at 12 weeks of age (MAP measured in conscious, chronically instrumented animals: 139±2 vs. 129±2 mmHg and T: 399±75 vs. 166±30ng/ml, P<0.01, IUGR vs. control, respectively). Gonadectomy (CTX) performed at 10 weeks of age abolished hypertension in IUGR offspring (MAP measured by telemetry from 13 weeks: 137±1 vs. 117±1 to 16 weeks: 144±1 vs. 123±2 mmHg, CTX vs. Sham, respectively). Thus, these results suggest that testosterone does play a role in modulating hypertension in male IUGR offspring, thus providing an excellent animal model to study sex hormone involvement in the fetal programming of HT. NIH HL074927.

Altered vascular function in fetal programming of hypertension.

Reduced endothelium-dependent vasorelaxation partly due to loss of nitric oxide (NO) bioavailability occurs in most cases of chronic hypertension. Intrauterine nutritional deprivation has been associated with increased risk for hypertension and stroke, associated with relaxant dysfunction and decreased vascular compliance, but the underlying mechanisms are not known. The present studies were undertaken to investigate whether endothelial dysfunction associated with altered NO-dependent vasodilatation pathways is also observed in a model of in utero programming of hypertension. Pregnant Wistar rats were fed a normal (18%), low (9%), or very low (6%) protein isocaloric diet during gestation. Vasomotor response of resistance cerebral microvessels (<50 micro m) was studied in adult offspring of dams fed the 18% and 9% protein diets by a video imaging technique. Endothelial NOS (eNOS), soluble guanylate cyclase (sGC), and K(Ca) channel expression were measured by Western blot. NO synthase (NOS) activity was measured enzymatically as well as in situ by NADPH diaphorase staining. Litter size and survival to adulthood were not affected by the diets. Birth weights of offspring of dams fed the 6% diet were markedly lower than those of dams fed the 9% diet, which were marginally lower than those of controls. Systolic blood pressures of adult offspring of mothers in the 6% and 9% groups were comparably greater (156+/-2 and 155+/-1 mm Hg, respectively) than that of control offspring (137+/-1 mm Hg); we therefore focused on the 9% and 18% groups. Cerebral microvessel constriction to thromboxane A(2) mimetic and dilation to carba-prostaglandin I(2) did not differ between diet groups. In contrast, vasorelaxation to the NO-dependent agents substance P and acetylcholine was diminished by 50% in low protein-exposed offspring, but eNOS expression and activity were similar between the 2 diet groups. Vasorelaxant response to the NO donor sodium nitroprusside was also decreased and was associated with reduced (by 50% to 65%) cGMP levels and sGC expression. cGMP analogues caused comparable vasorelaxation in the 2 groups. Expression of K(Ca) (another important mediator of NO action) and relaxation to the K(Ca) opener NS1619 were unchanged by antenatal diet. Maternal protein deprivation, which leads to hypertension in the offspring, is associated with diminished NO-dependent relaxation of major organ (cerebral) microvasculature, which seems to be largely attributed to decreased sGC expression and cGMP levels. The study provides an additional explanation for abnormal vasorelaxation in nutrient-deprived subjects in utero.

Excessive glucocorticoid exposure during late intrauterine development modulates the expression of cardiac uncoupling proteins in adult hypertensive male offspring.

We investigated the impact of intrauterine growth retardation and fetal programming of hypertension by maternal dexamethasone treatment on cardiac uncoupling protein (UCP) expression during development and in adulthood in the rat. Dexamethasone administered via an indwelling osmotic pump (100 micrograms/kg body mass per day from day 15 of gestation) decreased fetal body mass at day 21 of gestation (by 13%; P < 0.05), elicited significant (+24%, P < 0.01) systolic hypertension and elevated corticosterone levels (+15%; P < 0.05) in adult (24-week-old) male offspring. Cardiac UCP-2 and UCP-3 protein expression was significantly upregulated during early postnatal development, reaching 1.7-fold and 2.7-fold the respective fetal day-21 levels by postnatal day 7 and reaching plateaus at postnatal days 15-21 (2.5-fold and 3.5-fold of respective fetal levels). Cardiac UCP protein expression at fetal day 21 and the ontogeny of cardiac UCP expression during early postnatal life were unaffected by prenatal dexamethasone treatment. Prenatal dexamethasone treatment did not abrogate the postnatal surge in corticosterone levels or modify plasma non-esterified fatty acid (NEFA) levels over this period. However, UCP-2 and UCP-3 protein expression was significantly downregulated in the hearts of adult hypertensive male offspring of dexamethasone-treated mothers (to 27% and 65% of control values respectively). We propose that changes in cardiac UCP protein expression are linked with changes in cardiac metabolic fuel selection (from glucose-->fatty acids at birth and from fatty acids-->glucose during hypertension).