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Sex-Selective Increase of IGF-2 Expression in the Hypoxic Guinea Pig Placenta of Growth-Restricted Fetuses

  • Maternal Fetal Medicine/Biology: Original Article
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Abstract

Chronic hypoxia can cause fetal growth restriction (FGR) through placental dysfunction. Insulin-like growth factors (IGFs), such as IGF-2, play a major role in preservation of placental growth and function. We investigated the effects of chronic hypoxia and sex on protein expression of the IGF-2 pathway in placentas selected from asymmetric-FGR fetuses. Time-mated pregnant guinea pigs were assigned to normoxia (NMX, 21% O2) or hypoxia (HPX, 10.5% O2) during the last 14 days of pregnancy. Placentas were selected from male and female symmetrically grown NMX fetuses (fetal wt between 25th ile–75th ile) and HPX fetuses of asymmetric-FGR (fetal wt < 25th ile and brain:liver wt > 50th ile). Effects of HPX and sex on placenta protein expression of the IGF-2 signaling proteins (IGF-2, PI3K, AKT-P, total AKT, PCNA, a cell proliferation marker) were evaluated by immunoblotting. Effects of HPX and sex on morphometric parameters were analyzed using two-way ANOVA (p < 0.05). HPX reduced (p < 0.005) fetal wt by ~ 35% compared to NMX in both sexes. Expression of IGF-2 was lower (p = 0.029) in NMX female placentas compared to males. Despite lower NMX levels, HPX increased (p < 0.05) expression of IGF-2, AKT-P, relative AKT-P, and PCNA in female placentas only and had no effect on protein expression in male placentas. The female guinea pig placenta exhibits a greater sensitivity than males to HPX in upregulating expression of the IGF-2 axis. In addition, the sex difference in baseline IGF-2 expression suggests a greater capacity for females to increase IGF-2 in response to HPX as a placental adaptation in FGR.

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Funding

The project described is supported in part by a National Institute of Health (NIH HL126859, LPT) grant. The content is solely the responsibility of the authors and does not necessarily represent the official view of the National Institute of Health.

All animal procedures were approved by the University of Maryland Animal Care and Use Committee in accordance with the Association for Assessment and Accreditation of Laboratory Animal Care-accredited procedures (Animal Welfare Assurance No. A3200-01).

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  1. Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD, USA

    Emad A. Elsamadicy & Loren P. Thompson

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43032_2022_979_MOESM1_ESM.pptx

Supplementary file1 Figure 1. Western immunoblot of IGF-2 (MW=13kDa) expression in male and female placentas. Normoxic (NMX) (top) andhypoxic (HPX, 10.5% O2, 14 d) (bottom) placentas were loadedonto separate gels to compare differences due to sex. Each lane represents asingle placenta sample (N=7 for each group).Each target band was normalized to ß-actin (MW= 42 kDa) as a loadingcontrol. (PPTX 408 KB)

43032_2022_979_MOESM2_ESM.pptx

Supplementary file2 Figure 2. Western immunoblot of IGF-2 protein (MW=13kDa)expression in normoxic and hypoxic (10.5%O2, 14d) placentas. Male (top) and female (bottom)placentas were loaded onto separate gelsto compare the effects of treatment.Each lane represents a single placenta sample (N=7 for each). Each target band was normalized to ß-actin (MW=42 kDa) as a loading control. (PPTX 456 KB)

43032_2022_979_MOESM3_ESM.pptx

Supplementary file3 Figure 3. Western immunoblot ofphosphoinositide 3-kinase (PI3K, MW= 84 kDa) expression in normoxic and hypoxic(10.5%O2, 14d) placentas. Male(top) and female (bottom) placentas were loaded onto separategels to compare the effects of treatment.Each lane represents a single placenta sample (N=7 for each). Each target band was normalized to ß-actin (MW= 42 kDa) as a loading control. (PPTX 415 KB)

43032_2022_979_MOESM4_ESM.pptx

Supplementary file4 Figure 4. Western immunoblot of phosphorylated(AKT-P) and total protein kinase B (AKT-Total) expression in normoxic andhypoxic (10.5%O2, 14d) placentas.Male (top two images) and female (bottomtwo images) placentas were loaded onto separate gels to compare th effects oftreatment. For both male and femalesamples, membranes were first probed for AKT-P (MW=57kDa), stripped, and thenreprobed for AKT-Total (MW=57kDa). Each target band was normalized to ß-actin (MW= 42 kDa) as a loading control to obtain values for AKT-P and AKT-Total. Subsequently, AKT-P values were normalized toAKT-Total. Each lane represents a singleplacenta sample (N=7 for each group). (PPTX 803 KB)

43032_2022_979_MOESM5_ESM.pptx

Supplementary file5 Figure 5. Western immunoblot of proliferating cellnuclear antigen (PCNA, MW = 29kDa) expression in normoxic and hypoxic (10.5%O2,14d) placentas. Male (top) andfemale (bottom) placentas were loaded onto separate gels to compare theeffects of treatment. Each lanerepresents a single placenta sample (N=7 for each). Each target band was normalized to ß-actin (MW= 42 kDa) as a loading control. (PPTX 364 KB)

43032_2022_979_MOESM6_ESM.pptx

Supplementary file6 Figure 6: Western immunoblot offull membrane targeting IGF-2 and Beta actin of normoxic and hypoxic (10.5%O2,14d) male placentas. Top membrane identified IGF-2 targeted with a polyclonalantibody at a MW of 13kDa. Bottom imageidentifies the same membrane was stripped and re-probed for Beta actinidentified at a MW of 42kDa. (PPTX 1408 KB)

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Elsamadicy, E.A., Thompson, L.P. Sex-Selective Increase of IGF-2 Expression in the Hypoxic Guinea Pig Placenta of Growth-Restricted Fetuses. Reprod. Sci. 29, 3015–3025 (2022). https://doi.org/10.1007/s43032-022-00979-y

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