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Intrauterine growth restriction (IUGR) increases the risk of serious adult morbidities such as hypertension. In an IUGR rat model of hypertension, we reported a persistent decrease in kidney 11[beta]-hydroxysteroid dehydrogenase type 2 (l1[beta]-HSD2) mRNA and protein levels from birth through postnatal (P) day 21. This enzyme deficiency can lead to hypertension by limiting renal glucocorticoid deactivation. In the present study, we hypothesized that IUGR affects renal 11[beta]-HSD2 epigenetic determinants of chromatin structure and alters key transcription factor binding to the 11[beta]-HSD2 promoter in association with persistent downregulation of its mRNA expression. To test this hypothesis, we performed bilateral uterine artery ligation on embryonic day 19.5 pregnant rats and harvested kidneys at day 0 (P0) and P21. Key transcription factors that can affect l1[beta]-HSD2 expression include transcriptional enhancers specificity protein 1 (SP1) and NF-[kappa]B p65 and transcriptional repressors early growth response factor (Egr-1) and NF-[kappa]B p50. Our most important findings were as follows: 1) IUGR significantly decreased SP1 and NF-[kappa]B (p65) binding to the 11[beta]-HSD2 promoter in males, while it increased Egr-1 binding in females and NF-[kappa]B (p50) binding in males; 2) IUGR increased CpG methylation status, as well as modified the pattern of methylation in several CpG sites of 11[beta]-HSD2 promoter at P0 also in a sex-specific manner; and 3) IUGR decreased trimethylation of H3K36 in exon 5 of 11[beta]-HSD2 at P0 and P21 in both genders. We conclude that IUGR is associated with altered transcriptional repressor/activator binding in connection with increased methylation in the 11[beta]-HSD2 promoter region in a sex-specific manner, possibly leading to decreased transcriptional activity. Furthermore, IUGR decreased trimethylation of H3K36 of the l1[beta]-HSD2 gene in both genders, which is associated with decreased transcriptional elongation. We speculate that alterations in transcription factor binding and chromatin structure play a role in in utero reprogramming. hypertension; gene transcription; histone acetylation; deoxyribonucleic acid methylation doi: 10.1152/ajpregu.00122.2010.

Effects of restricting uterine space on physical, biochemical, and histochemical characteristics of ovine placental tissues were studied. Ewes (n = 20) were unilaterally ovariectomized, assigned to either control (C; n = 10) or unilateral (UPx; n = 10) pregnancy groups, mated (d 0), and hysterectomized on either d 60, 90, or 120. Placental and fetal weights and placentome wet weights (PWT) in three placental areas (AI, AII, AIII) were recorded. Placentome tissue concentrations of RNA, DNA, hyaluronic acid (HA), and protein (TP) were determined. Overall, placentome numbers were reduced (P < .02) 23%, but individual PWT increased (P < .05) 27% in UPx ewes. In UPx ewes, neither total placental nor placentome weights, fetal weights, fetal crown-rump lengths, nor PWT:fetal weight ratios were affected by treatment (Trt). In the C and UPx groups, PWT increased (P < .01) from d 60 to 90. However, compensatory growth was confined to placental areas AII and Alii in UPx groups (treatment x area, P < .01). Treatment did not affect concentrations of RNA, DNA, TP, or HA. However, RNA, DNA, and TP increased from d 60 to 120 (P < .01), but HA decreased (P < .01). Histologically, placentome cellularity increased from d 60 to 120 as area occupied by individual fetal chorioallantoic villi (FV) decreased. The FV stained with Alcian Blue 8X. Alcianophilia was attenuated at low pH and eliminated by pretreatment with hyaluronidase, indicating the presence of HA. Thus, increased placentomal cellularity was accompanied by loss of HA from fetal allantoic mesenchyme. Mechanisms regulating loss of HA from FV may support placental maturation and fetal growth. Key Words: Sheep, Placenta, Growth, Glycosaminoglycans, Hyaluronic Acid

A modified version of the coronary embolization technique that eliminates the need for thoracoscopy is used to produce chronic left ventricular (LV) dysfunction in rats with symptoms resembling that of coronary ligation. Aorto-caval fostula is suitable for producing myocardial hypertrophy, characterized by enhanced plasma atrial natriuretic factor. The evaluation of LV performance and clear presence of systolic and/or diastolic dysfunction are crucial to render the above models as accurate representations of heart failure.