Full-length human placental sFlt-1-e15a isoform induces distinct maternal phenotypes of preeclampsia in mice

• Published in: PloS one Vol. 10; no. 4; p. e0119547
• Main Authors: Szalai, Gabor, Romero, Roberto, Chaiworapongsa, Tinnakorn, Xu, Yi, Wang, Bing, Ahn, Hyunyoung, Xu, Zhonghui, Chiang, Po Jen, Sundell, Birgitta, Wang, Rona, Jiang, Yang, Plazyo, Olesya, Olive, Mary, Tarca, Adi L, Dong, Zhong, Qureshi, Faisal, Papp, Zoltan, Hassan, Sonia S, Hernandez-Andrade, Edgar, Than, Nandor Gabor
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 10.04.2015; Public Library of Science (PLoS)
• Subjects: Adenoviruses; Age; Albumin; Amino Acid Sequence; Angiogenesis; Animal models; Animals; Aorta; Blood; Blood Pressure; Blood Pressure Monitors; Carotid artery; Catheters; Cell adhesion & migration; Cesarean section; Childrens health; Creatinine; Disease Models, Animal; Female; Fetuses; Fluorescence; Gene Expression Profiling; Gestational Age; Green fluorescent protein; Green Fluorescent Proteins - genetics; Gynecology; Humans; Hypertension; Liver; Liver diseases; Medical research; Medicine; Mice; Mice, Transgenic; Molecular Sequence Data; Monitoring; Obstetrics; Pathology; Phenotype; Placenta; Placenta - diagnostic imaging; Placenta - pathology; Placenta - physiopathology; Postpartum; Pre-eclampsia; Pre-Eclampsia - etiology; Pre-Eclampsia - pathology; Pre-Eclampsia - physiopathology; Preeclampsia; Pregnancy; Pressure measurement; Pressure measurements; Protein Isoforms - administration & dosage; Protein Isoforms - genetics; Protein Isoforms - physiology; Protein-tyrosine kinase; Recombinant Proteins - administration & dosage; Recombinant Proteins - genetics; RNA, Messenger - genetics; RNA, Messenger - metabolism; Rodents; Sequence Homology, Amino Acid; Species Specificity; Surgery; Surgical implants; Survival; Telemetry; Tyrosine; Ultrasonography; Ultrasound; Urine; Vascular Endothelial Growth Factor Receptor-1 - administration & dosage; Vascular Endothelial Growth Factor Receptor-1 - genetics; Vascular Endothelial Growth Factor Receptor-1 - physiology
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0119547

Most anti-angiogenic preeclampsia models in rodents utilized the overexpression of a truncated soluble fms-like tyrosine kinase-1 (sFlt-1) not expressed in any species. Other limitations of mouse preeclampsia models included stressful blood pressure measurements and the lack of postpartum monitoring. We aimed to 1) develop a mouse model of preeclampsia by administering the most abundant human placental sFlt-1 isoform (hsFlt-1-e15a) in preeclampsia; 2) determine blood pressures in non-stressed conditions; and 3) develop a survival surgery that enables the collection of fetuses and placentas and postpartum (PP) monitoring. Pregnancy status of CD-1 mice was evaluated with high-frequency ultrasound on gestational days (GD) 6 and 7. Telemetry catheters were implanted in the carotid artery on GD7, and their positions were verified by ultrasound on GD13. Mice were injected through tail-vein with adenoviruses expressing hsFlt-1-e15a (n = 11) or green fluorescent protein (GFP; n = 9) on GD8/GD11. Placentas and pups were delivered by cesarean section on GD18 allowing PP monitoring. Urine samples were collected with cystocentesis on GD6/GD7, GD13, GD18, and PPD8, and albumin/creatinine ratios were determined. GFP and hsFlt-1-e15a expression profiles were determined by qRT-PCR. Aortic ring assays were performed to assess the effect of hsFlt-1-e15a on endothelia. Ultrasound predicted pregnancy on GD7 in 97% of cases. Cesarean section survival rate was 100%. Mean arterial blood pressure was higher in hsFlt-1-e15a-treated than in GFP-treated mice (∆MAP = 13.2 mmHg, p = 0.00107; GD18). Focal glomerular changes were found in hsFlt-1-e15a -treated mice, which had higher urine albumin/creatinine ratios than controls (109.3 ± 51.7 μg/mg vs. 19.3 ± 5.6 μg/mg, p = 4.4 x 10(-2); GD18). Aortic ring assays showed a 46% lesser microvessel outgrowth in hsFlt-1-e15a-treated than in GFP-treated mice (p = 1.2 x 10(-2)). Placental and fetal weights did not differ between the groups. One mouse with liver disease developed early-onset preeclampsia-like symptoms with intrauterine growth restriction (IUGR). A mouse model of late-onset preeclampsia was developed with the overexpression of hsFlt-1-e15a, verifying the in vivo pathologic effects of this primate-specific, predominant placental sFlt-1 isoform. HsFlt-1-e15a induced early-onset preeclampsia-like symptoms associated with IUGR in a mouse with a liver disease. Our findings support that hsFlt-1-e15a is central to the terminal pathway of preeclampsia, and it can induce the full spectrum of symptoms in this obstetrical syndrome.