In a model of growth-restricted sheep pregnancy, it was previously demonstrated that transient uterine artery VEGF overexpression can improve fetal growth. This approach was tested in guinea-pig pregnancies, where placental physiology is more similar to humans. Fetal growth restriction (FGR) was attained through peri-conceptual nutrient restriction in virgin guinea pigs. Ad.VEGF-A or Ad.LacZ (1 × 10vp) was applied at mid-gestation via laparotomy, delivered externally to the uterine circulation with thermosensitive gel. At short-term (3-8 days post surgery) or at term gestation, pups were weighed, and tissues were sampled for vector spread analysis, VEGF expression, and its downstream effects. Fetal weight at term was increased (88.01 ± 13.36 g; n = 26) in Ad.VEGF-A-treated animals compared with Ad.LacZ-treated animals (85.52 ± 13.00 g; n = 19; p = 0.028). The brain, liver, and lung weight and crown rump length were significantly larger in short-term analyses, as well as VEGF expression in transduced tissues. At term, molecular analyses confirmed the presence of VEGF transgene in target tissues but not in fetal samples. Tissue histology analysis and blood biochemistry/hematological examination were comparable with controls. Uterine artery relaxation in Ad.VEGF-A-treated dams was higher compared with Ad.LacZ-treated dams. Maternal uterine artery Ad.VEGF-A increases fetal growth velocity and term fetal weight in growth-restricted guinea-pig pregnancy.
Our study aimed to target adenoviral gene therapy to the uteroplacental circulation of pregnant guinea pigs in order to develop a novel therapy for fetal growth restriction. Four methods of delivery of an adenovirus encoding β-galactosidase (Ad.LacZ) were evaluated: intravascular injection using phosphate-buffered saline (PBS) into (1) uterine artery (UtA) or (2) internal iliac artery or external administration in (3) PBS or (4) pluronic F-127 gel (Sigma Aldrich). Postmortem examination was performed 4 to 7 days after gene transfer. Tissue transduction was assessed by X-gal histochemistry and enzyme-linked immunosorbent assay. External vascular application of the adenovirus vector in combination with pluronic gel had 91.7% success rate in terms of administration (85% maternal survival) and gave the best results for maternal/fetal survival and local transduction efficiency without any spread to maternal or fetal tissues. This study suggests an optimal method of gene delivery to the UtAs of a small rodent for preclinical studies.
Fetal growth restriction (FGR) is a common and potentially severe pregnancy complication. Currently there is no treatment available. The guinea pig is an attractive model of human pregnancy as placentation is morphologically very similar between the species. Nutrient restriction of the dam creates growth-restricted fetuses while leaving an intact uteroplacental circulation, vital for evaluating novel therapies for FGR. Growth-restricted fetuses were generated by feeding Dunkin Hartley guinea pig dams 70% of ad libitum intake from four weeks before and throughout pregnancy. The effect of maternal nutrient restriction (MNR) on dams and fetuses was carefully monitored, and ultrasound measurements of pups collected. There was no difference in maternal weight at conception, however by five weeks post conception MNR dams were significantly lighter ( P < 0.05). MNR resulted in significantly smaller pup size from 0.6-0.66 gestation. Ultrasound is a powerful non-invasive tool for assessing the effect of therapeutic interventions on fetal growth, allowing longitudinal measurement of fetuses. This model and method yield data applicable to the human condition without the need for animal sacrifice and will be useful in the translation of therapies for FGR into the clinic.
Introduction Fetal growth restriction (FGR) is commonly caused by impaired utero-placental perfusion. Adenovirus (Ad) mediated over-expression of VEGF-A165 in the uterine arteries (UtAs) of pregnant sheep significantly increases UtA blood flow, compared with UtAs transduced with a control adenovirus encoding β-galactosidase (Ad.LacZ). In FGR sheep, UtA injection of Ad.VEGF-A165 significantly improves fetal growth velocity. Aim To study if Ad.VEGF-A165 transduction enhances fetal growth in the FGR guinea pig. Methods To create FGR, virgin Dunkin-Hartley guinea pigs were nutrient restricted peri-conceptually. Under general anaesthesia at mid-gestation (30-34 days), sonographic fetal measurements were recorded in FGR guinea pigs and control ad lib fed sows. At laparotomy the UtAs and radial arteries on each side were transduced externally with Ad.VEGF-A165 or Ad.LacZ (5x109 viral particles), using a thermosensitive pluronic gel. Guinea pigs were sacrificed 31-34 days post-surgery but before birth. Fetal organ weights and biometry were recorded. Results Nutrient restriction reduced fetal weight by 40%, with brain sparing. In FGR pregnancies, administration of Ad.VEGF-A165 increased fetal weight(94.5 ± 2.01g, n=11) compared to control Ad.LacZ treated fetuses (84.9 ± 2.81g, n=10, p=0.061). The liver and kidneys were significantly heavier in the Ad.VEGF-A165 group (5.6 ± 0.23g v/s 4.7 ± 0.18g, p=0.019 and 0.74 ± 0.065g v/s 0.37 ± 0.021g, p<0.001 respectively), and the brain/liver weight ratio was significantly lower (0.45 ± 0.019 v/s 0.53 ± 0.017, p=0.021), suggesting an attenuated brain sparing effect. Conclusion VEGF gene therapy targeted to the utero-placental vasculature reduces brain sparing and may enhance fetal growth in FGR guinea pig pregnancy, and is a potential treatment for severe FGR.
I. HISTORICALA s p e m : (a) the period from 1907 to the reat depression of 1929-32.; (b) the period from 1929-32 to k c commencement of the second world war; (c) the period of the second world war, 1939-45; (d) the immediate post-war period, 1945-1952/53; a) the period from 1953 to 1958-59; and 1. Wine Board re ort (unpublished) on "The clothinn industry. Wltwatcnrand and Pretoria". dmted 20th July, i. C a b f o r a . Port Elizabeth. East London, Durbnn. 1929 pnrni 6 I6 mnd 'fable A.Kingwilliamstown and Durban.' The industry was described as highly competitive, not only internally but also in relation to very severe foreign competition. Throughout the Union, total employment in the wholesale industry then stood at 6,410, comprising 2,717 on the Witwatersrand; 2,677 in the Cape Peninsula; 481 in Durban and Pietermaritzburg; 222 in Kingwilliamstown and East London; and 57 in Worcester. The locational pattern so depicted remained typical of the industry for another 20 years. Analysis of the racial distribution shows that European workers were then slightly in the majority at 3,454, followed by 2,261 Coloureds, 513 natives and 182 Asiatics. At that stage the diversification of the industry's products had not progressed very far. Men's and boys' outerwear in the fonn of suits, flannel trousers, jackets and overcoats constituted the main products, for which the Witwatersrand was the most important centre. Shirt and pyjama manufacture was well advanced, with Cape Town in the lead. The making of both men's and women's underwear was developing fairly rapidly at Cape Town and Johannesburg, and ties, hats, caps and hosiery were all being produced in quantity. Knitwear was being made in all the main centres, though not on a large scale. The first dress factory of importance commenced operations in Johannesburg only in 1931, though the subsequent development of the women's outerwear section became a feature of the later 1930's and early 1940's.
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