Mechanisms of Pregnancy Vascular Adaptations

Angiotensin 2 Receptor (AT2R) Expression/Activation in Endothelial Cells in Preeclampsia

The investigators will collect omental tissue (research surgical excision) and placental tissue (standard of care clinical delivery) from both preeclamptic and non-preeclamptic women during their c-section and use these samples to study the blood vessels, specifically the expression/activation of the AT2R.

Study Overview

• Status: Recruiting
• Conditions: Vascular Diseases; Pre-Eclampsia
• Intervention / Treatment: Procedure: Omental Biopsy

Detailed Description

Trial Design: The study is a comparison of two cohorts, those with and without preeclampsia during pregnancy. The team plans to investigate role of FABP4, PFAS and AT2 in modulation of vascular function/dysfunction using vessels isolated from the omental biopsies. The investigators will examine for the evidence of fetal vascular dysfunction mediated by decreased expression of AT2 in preeclampsia using vessels isolated from the placentas.

Study Population: The study will include pregnant women. The pregnant women will participate in the omental tissue collection, placenta collection, and the medical record review.

The study is expects a maximum enrollment of 114 pregnant women. This is because 52 omental biopsies and 52 placentas are required to meet proposed statistical considerations. Participants have the option of providing just one or both of the specimens. There is a possibility as few as 52 participants could be enrolled and a maximum of 104 participants could be enrolled to meet this requirement. There is an additional 10 participants enrollment built into the enrollment number to allow for replacement of subjects based on lack of clinical data in some participants, failure of tissue viability and hence experiments, and thus a maximum of 114 (104+10) participants could be enrolled.

This required enrollment (52) is divided into two cohorts based on the diagnosis of preeclampsia: 26 of each type of specimen in which the woman was diagnosed with preeclampsia during her pregnancy, and 26 of each type of specimen in which the woman was not diagnosed with preeclampsia during her pregnancy. Additionally, each cohort of 26 will be divided into two groups based on gender of the fetus, 13 male fetuses and 13 female fetuses

• Study Type: Observational
• Enrollment (Estimated): 114

Contacts and Locations

• Study Contact: Name: Sharon E Blohowiak, MS; Phone Number: 6084176957; Email: sblohowiak@wisc.edu
• Study Contact Backup: Name: Rosalina Boeldt; Phone Number: 608-417-4232; Email: villalonland@wisc.edu

Study Locations

• United States
  • Wisconsin
    • Madison, Wisconsin, United States, 53715
      • Recruiting
      • UnityPoint Health-Meriter Hospital
      • Contact: Sharon Blohowiak; Phone Number: 608-417-6957; Email: sblohowiak@wisc.edu
      • Principal Investigator: Sathish Kumar, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 38 years (Adult)
• Accepts Healthy Volunteers: N/A

• Sampling Method: Non-Probability Sample

Study Population

Pregnant women with or without Preeclampsia who will be undergoing a C-section

Description

Inclusion Criteria:

• female
• Minimum age: 18
• Maximum age: 40
• Singleton births
• Minimum gestational age at consent: 28 weeks, 0 days
• Maximum gestational age at consent: 41 weeks, 0 days
• Undergoing caesarean section, either planned or otherwise with or without trial of labor

Exclusion Criteria:

• Preexisting hypertension treated by antihypertensive agents during the prenatal period. This will not include treatment of severe hypertension by antihypertensive or use of magnesium sulfate after the patient is hospitalized for the diagnosis of preeclampsia.
• Any major fetal structural anomalies or aneuploidies
• Preexisting conditions like pre-gestational type I or type II diabetes mellitus, pre-pregnancy kidney disease with increased serum creatinine above 1.2 mg/dL, or other underlying blood vessel problems like systemic lupus erythematosus or other autoimmune conditions with evidence of pre-pregnancy proteinuria or hypertension.
• Undergoing cesarean section for placental abruption or bleeding complications.
• Singleton gestation not within 36 weeks, 0 days and 41 weeks, 0 days gestational age at the time of enrollment (delivery)

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Cohort 1 no Preeclampsia; Cohort 1: 26 mothers with no diagnosis of preeclampsia during pregnancy (13 male, 13 female neonate) Omental Biopsy and placental collection will be performed	Procedure: Omental Biopsy; The surgeon and clinical care team will conduct the c-section to deliver the baby and the placenta as clinically indicated. After delivery, during the closing procedures, the surgeon will indicate a time for a participating Ob/Gyn physician on the study team to collect the omental bio-specimen. Omentum is frequently excised or removed for clinical reasons during surgical procedures. Omentum has small blood vessels within it that have been used for evaluation of vascular functional changes in research. The investigators wish to isolate one to three vessels of 5 to 7 cm length. The surgeon will then close and the clinical care team will resume their standard of care activities.
Cohort 2 mild or severe Preeclampsia; Cohort 2: 26 mothers with diagnosis of mild or severe preeclampsia during pregnancy (13 male, 13 female neonate) Omental Biopsy and placental collection will be performed	Procedure: Omental Biopsy; The surgeon and clinical care team will conduct the c-section to deliver the baby and the placenta as clinically indicated. After delivery, during the closing procedures, the surgeon will indicate a time for a participating Ob/Gyn physician on the study team to collect the omental bio-specimen. Omentum is frequently excised or removed for clinical reasons during surgical procedures. Omentum has small blood vessels within it that have been used for evaluation of vascular functional changes in research. The investigators wish to isolate one to three vessels of 5 to 7 cm length. The surgeon will then close and the clinical care team will resume their standard of care activities.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quantify the vascular AT2R expression and vascular function in placental and omental vascular arteries in both preeclamptic and controlled pregnancies.	The researchers will measure the amount and distribution of vascular angiotensin II type 1 receptor (AT1R) and AT2R during normal human pregnancy and in preeclampsia. The researchers will assess if AT2R expression varies with severity of preeclampsia. Based on pilot data, the researchers expect decreased AT2R and increased AT1R protein levels in preeclamptic vs normotensive vessels.	1 year
To test if ex-vivo treatment of AT2R agonists reverses the endothelial dysfunction and improves vasoconstriction in the preeclamptic vessels.	The researchers will quantify vascular AT2R expression and vascular function in placental and omental arteries of preeclamptic vs normal pregnant women. Vascular function studies will also test if ex vivo treatment with AT2R agonist reverses endothelial dysfunction and vasoconstriction in preeclamptic vessels.	1 year
To test AT2R mediated mechanisms on endothelial derived hyperpolarizing factor, nitric oxide and prostacyclin pathway of vascular relaxation to examine AT2's role in vaso-relaxation and AT2R mediated vasoconstrictor pathway will be defined.	To test the AT2R-mediated mechanisms, endothelium-derived hyperpolarizing factor (EDHF), nitric oxide, and prostacyclin (PGI2) pathways of vascular relaxation and AT1R-mediated vasoconstrictor pathways will be determined. Also, the expression of endothelial nitric oxide synthase, its activity state, and signaling components of EDHF and PGI2 pathways, as well as nitrate/nitrite and PGI2 production and changes in membrane potential, will be measured	1 year

Collaborators and Investigators

• Sponsor: University of Wisconsin, Madison
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Sathish Kumar, PhD, University of Wisconsin, Madison

Study record dates

Study Major Dates

• Study Start (Actual): November 20, 2018
• Primary Completion (Estimated): April 1, 2027
• Study Completion (Estimated): April 1, 2027

Study Registration Dates

• First Submitted: January 14, 2019
• First Submitted That Met QC Criteria: January 14, 2019
• First Posted (Actual): January 16, 2019

Study Record Updates

• Last Update Posted (Actual): October 19, 2023
• Last Update Submitted That Met QC Criteria: October 18, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Pregnancy Complications; Hypertension, Pregnancy-Induced; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Vascular Diseases; Eclampsia; Pre-Eclampsia
• Other Study ID Numbers: Meriter IRB 2018-006; A532860 (Other Identifier: UW Madison); 5R01HL134779-02 (U.S. NIH Grant/Contract); SMPH/OBSTET & GYNECOL/OBSTET (Other Identifier: UW Madison); 2018-1368 (Other Identifier: UW-Madison IRB); Protocol Version 2/7/2023 (Other Identifier: Meriter IRB)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No