# Vascular Mechanisms of Hypertension-in-Pregnancy

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $722,697

## Abstract

Project Summary/Abstract
 Preeclampsia (PE) is a complication of pregnancy characterized by hypertension (HTN-Preg) and
intrauterine growth restriction (IUGR), with unclear mechanism and limited remedies. We and others have
shown that: reduction in uterine perfusion pressure (RUPP) and infusion of sFlt-1 or TNF in pregnant (Preg)
rats reduce vascular relaxation and increase vasoconstriction (VC) and BP; however, the vascular and uterine
targets are unclear. Normal pregnancy involves extensive uteroplacental and vascular remodeling, and matrix
metalloproteinases (MMPs) and related A Disintegrin And Metalloprotease (ADAM) family maintain adequate
tissue remodeling. We have found decreases in uteroplacental and vascular MMP-2 and -9, and increases in
MMP-1 and -7 in RUPP, and sFlt-1 and TNF infused Preg rats. We have also discovered that MMPs not only
degrade extracellular matrix (ECM) proteins, but also release peptide fragments, growth factors and ET-1 and
in turn affect the Endothelium, Vascular smooth muscle (VSM) and ECM (EVE), such that MMP-2 and -9 are
vasodilators (VD) while MMP-1 and -7 are vasoconstrictors (VC). Also, in search for the upstream mechanisms
that trigger the changes in MMPs, our data suggest that ADAM-17, a sheddase and TNF converting enzyme,
is increased in RUPP rats, and elevation of ADAM-17 causes MMP imbalance, and increases circulating TNF
and sFlt-1, VC and BP in Preg rats. These new findings led us to the novel hypothesis that disruption of VD/VC
MMP balance is a major mechanism of impaired EVE-dependent vascular pathways and HTN-Preg. Increased
ADAM-17 activity triggers disruption of MMP balance. Consequently, correcting MMP imbalance by
upregulating VD MMP-2 and -9 or downregulating VC MMP-1 and -7, or reducing the upstream ADAM-17
activity should improve EVE-dependent vascular pathways and HTN-Preg. Studies will be performed on Preg
rats; RUPP, sFlt-1 and TNF-infused rat models of HTN-Preg; Preg rats treated with MMP-2 and -9 inhibitors,
neutralizing antibody or siRNA or with ADAM-17, MMP-1 or -7; and MMP-2, -9 and -7 KO mice. Mechanistic
studies at the whole animal, uteroplacental, microvascular and molecular levels will provide in-depth analysis
of the mechanisms linking ADAM-17 and MMP imbalance to impaired EVE-dependent vascular pathways and
HTN-Preg. The specific aims are to test the hypotheses that: 1) Disruption of VD/VC MMP balance during
pregnancy is sufficient to impair EVE-dependent vascular pathways and cause HTN-Preg. 2) Increased
ADAM-17 activity is an upstream mechanism that triggers disruption of VD/VC MMP balance, leading to
impaired EVE-dependent vascular pathways and HTN-Preg. 3) Interventional correction of MMP imbalance
and ADAM-17 activity is a central target to improve EVE-dependent vascular pathways and HTN-Preg. These
studies should provide a better understanding of the role of MMP imbalance and ADAM-17 in HTN-Preg, and
highlight potential usefulness of correcting MMP imbalance and ADAM...

## Key facts

- **NIH application ID:** 10396170
- **Project number:** 5R01HL147889-02
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Raouf A Khalil
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $722,697
- **Award type:** 5
- **Project period:** 2020-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10396170

## Citation

> US National Institutes of Health, RePORTER application 10396170, Vascular Mechanisms of Hypertension-in-Pregnancy (5R01HL147889-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10396170. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*