Long-term increase in uterine blood flow is achieved by local overexpression of VEGF-A165 in the uterine arteries of pregnant sheep

Mehta,; Abi-Nader, K; Peebles, Donald; Benjamin, E.; Wigley,; Torondel, Belén; Filippi, Elisa; Shaw, Sheng-Wen; Boyd, Michael; Martin, John F.; Zachary, Ian; David, Anna L.

doi:10.1038/gt.2011.158

Cited by 53 publications

(65 citation statements)

References 55 publications

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“…These results contrasted with our previous organ bath findings in UtA branches from normal sheep pregnancies, which demonstrated a reduced contractile response in Ad.VEGFtransduced vessels at both short-term and long-term time points: 4-7 days and 30-45 days posttreatment, respectively (David et al, 2008;Mehta et al, 2011). Moreover, there was a strikingly enhanced relaxation response to bradykinin relative to all other groups.…”

Section: Discussionmentioning

confidence: 86%

“…Both aspects indicate with hindsight that the telemetric Physiogear system was not functioning optimally and probably lacked the required sensitivity and precision to detect both the expected differences between nutritional groups and the impact of Ad.VEGF treatment. In addition, the assumption of a 50% increase in UBF after Ad.VEGF treatment was based on a previous study in normally developing pregnancies with a very different experimental design, having compared effects of Ad.VEGF injection into one UtA with Ad.LacZ injection into the opposite UtA of the same animal (Mehta et al, 2011). The increase in UBF was expressed as a percentage change from baseline values within the same animal using flow probes, which has been determined over 4-7 days before gene therapy administration.…”

Section: Discussionmentioning

confidence: 99%

“…To assess neovascularization, sections of UtA1-3 from all animals were immunostained with the endothelial cell marker anti-von Willebrand factor (1:200), as described (Mehta et al 2011). Slides were examined at · 20 magnification to identify the perivascular adventitia.…”

Section: Laboratory Analysesmentioning

confidence: 99%

“…Control-intake ewes all received saline (C + Saline, n = 12). Between 92 -0.2 and 130 -0.2 days of gestation, UBF was measured continuously for 45 min on alternate days telemetrically, as described (Mehta et al, 2011).…”

Section: Gene Therapymentioning

confidence: 99%

“…VEGF is an important biological agent that induces vasodilatation, angiogenesis, and vascular protection (Holmes and Zachary, 2005). Previous work in normal midgestation sheep pregnancies demonstrated a significant increase in UBF after UtA injection of Ad.VEGF-A 165 , which was sustained for up to 4 weeks (Mehta et al, 2011). Ad.VEGF-A 165 upregulated endothelial nitric oxide synthase (eNOS) expression in the UtA, and Ad.VEGF-A 165 -treated vessels demonstrated an enhanced vasodilator response to bradykinin and neovascularization within the perivascular adventitia (David et al, 2008).…”

Section: Introductionmentioning

confidence: 98%

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Uteroplacental Adenovirus Vascular Endothelial Growth Factor Gene Therapy Increases Fetal Growth Velocity in Growth-Restricted Sheep Pregnancies

Carr

Wallace²,

Aitken³

et al. 2014

Human Gene Therapy

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Fetal growth restriction (FGR) occurs in ∼8% of pregnancies and is a major cause of perinatal mortality and morbidity. There is no effective treatment. FGR is characterized by reduced uterine blood flow (UBF). In normal sheep pregnancies, local uterine artery (UtA) adenovirus (Ad)-mediated overexpression of vascular endothelial growth factor (VEGF) increases UBF. Herein we evaluated Ad.VEGF therapy in the overnourished adolescent ewe, an experimental paradigm in which reduced UBF from midgestation correlates with reduced lamb birthweight near term. Singleton pregnancies were established using embryo transfer in adolescent ewes subsequently offered a high intake (n=45) or control intake (n=12) of a complete diet to generate FGR or normal fetoplacental growth, respectively. High-intake ewes were randomized midgestation to receive bilateral UtA injections of 5×10¹¹ particles Ad.VEGF-A165 (n=18), control vector Ad.LacZ (n=14), or control saline (n=13). Fetal growth/well-being were evaluated using serial ultrasound. UBF was monitored using indwelling flowprobes until necropsy at 0.9 gestation. Vasorelaxation, neovascularization within the perivascular adventitia, and placental mRNA expression of angiogenic factors/receptors were examined using organ bath analysis, anti-vWF immunohistochemistry, and qRT-PCR, respectively. Ad.VEGF significantly increased ultrasonographic fetal growth velocity at 3-4 weeks postinjection (p=0.016-0.047). At 0.9 gestation fewer fetuses were markedly growth-restricted (birthweight >2SD below contemporaneous control-intake mean) after Ad.VEGF therapy. There was also evidence of mitigated fetal brain sparing (lower biparietal diameter-to-abdominal circumference and brain-to-liver weight ratios). No effects were observed on UBF or neovascularization; however, Ad.VEGF-transduced vessels demonstrated strikingly enhanced vasorelaxation. Placental efficiency (fetal-to-placental weight ratio) and FLT1/KDR mRNA expression were increased in the maternal but not fetal placental compartments, suggesting downstream effects on placental function. Ad.VEGF gene therapy improves fetal growth in a sheep model of FGR, although the precise mechanism of action remains unclear.

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Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Laboratory Analysesmentioning

confidence: 99%

Section: Gene Therapymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

See 3 more Smart Citations

Uteroplacental Adenovirus Vascular Endothelial Growth Factor Gene Therapy Increases Fetal Growth Velocity in Growth-Restricted Sheep Pregnancies

Carr

Wallace²,

Aitken³

et al. 2014

Human Gene Therapy

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Prospects for Prenatal Gene Therapy

Coutelle

2014

Encyclopedia of Life Sciences

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Somatic prenatal gene therapy (PGT) aims at treatment/prevention of progressive tissue/organ damage in early‐manifesting life‐threatening and otherwise incurable genetic diseases. Preclinical investigations applying different vectors and transgenes on several animal models including nonhuman primates have shown PGT to provide better access to target cells and their progenitors, induce tolerance to vector/transgenic protein and reduce the required amount of vector in comparison to postnatal gene therapy. Human application of PGT is now technically possible, however, safety issues regarding potential adverse effects on fetal development, oncogenesis‐induction and germline transmission as well as ethical considerations concerning risk–benefit assessment and alternative reproductive choices have so far prohibited human trials. Increasing the safety profile, for example, by use of novel vector systems and long‐time primate safety/efficiency studies, may prospectively validate PGT for selected human applications. High standards regarding information given to prospective patients (informed consent) and to the public on the aims, benefits and remaining risks will play an important role in any future clinical application of PGT. Key Concepts: Somatic gene therapy addresses genetic diseases of the treated individual at the level of the molecular defect. Prenatal gene therapy of early onset genetic disease prevents irreparable damage to tissues and organs and induces postnatal tolerance to therapeutic transgenic proteins. Prenatal gene delivery can reach proliferating precursor cell compartments more effectively than postnatal gene therapy. Different animal models including models of human genetic disease are required to establish optimal vectors and routes for gene delivery including those applicable in humans, to demonstrate the therapeutic efficiency of the delivered gene therapy, and to monitor and investigate the occurrence of potential adverse effects. In utero gene therapy could provide an alternative to termination of pregnancy or acceptance of an affected child after prenatal diagnosis of a genetically affected fetus, or to in vitro fertilisation followed by embryo selection in families with preconceptional knowledge of a specific genetic risk. Current options to avoid birth of a genetically affected child (termination of pregnancy, preimplantation diagnosis/embryo selection) impose very high demands on the outcome of human prenatal gene therapy with respect to its level of safety and effectiveness. Ethical considerations regarding the assessment and communication of the risks and benefits of prenatal gene therapy and its perception by affected families, the medical profession and the general public will play an important part in decisions on the clinical application of this novel therapeutic approach.

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Effect of vascular endothelial growth factor on fetal vessels among obese pregnant women

Janbakhishov

Çağlayan

Acet

et al. 2020

Intl J Gynecology & Obste

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Objective: To determine the role of vascular endothelial growth factor (VEGF) in placental hypoperfusion in obesity. Methods: The prospective study enrolled women with a first-trimester singleton pregnancy in Izmir, Turkey, between January and April 2011. Participants were divided into three groups: obese (body mass index [BMI, calculated as weight in kilograms divided by the square of height in meters] >30) with cesarean delivery; normal weight (BMI <30) with vaginal delivery (NVD); and healthy controls (BMI <30) with cesarean delivery. Before delivery, serum C-reactive protein (CRP), and uterine and fetal Doppler measurements were taken. VEGF was evaluated immunohistochemically from the umbilical cord. Results: Overall, 109 women completed the study: obesity group (n=13, 11.9%), NVD group (n=50, 45.9%), and control group (n=46, 42.2%). Serum CRP was higher in the obesity group than in the control or NVD groups (P=0.009). VEGF score was highest in the NVD group (9.39 ± 3.11), and lowest in the obesity group (4.58 ± 2.78) (P<0.001). VEGF score decreased by 0.81 for each increase in BMI of 1 (P=0.002). Conclusions: Maternal obesity was related to decreased VEGF expression. Although not supported by Doppler findings, decreased VEGF expression owing to maternal obesity might trigger endothelial dysfunction and inflammation.

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Long-term increase in uterine blood flow is achieved by local overexpression of VEGF-A165 in the uterine arteries of pregnant sheep

Cited by 53 publications

References 55 publications

Uteroplacental Adenovirus Vascular Endothelial Growth Factor Gene Therapy Increases Fetal Growth Velocity in Growth-Restricted Sheep Pregnancies

Uteroplacental Adenovirus Vascular Endothelial Growth Factor Gene Therapy Increases Fetal Growth Velocity in Growth-Restricted Sheep Pregnancies

Prospects for Prenatal Gene Therapy

Effect of vascular endothelial growth factor on fetal vessels among obese pregnant women

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