# Placental Ischemia, Hypertension and Hemodyanmics

> **NIH NIH R01** · UNIVERSITY OF MISSISSIPPI MED CTR · 2020 · $436,757

## Abstract

Cerebral vascular changes play a significant role in the pathogenesis of preeclampsia with cerebrovascular
events contributing to ~40% of all preeclampsia/eclampsia deaths. Little is understood about the underlying
causative mechanisms. Several studies suggest that impaired cerebral blood flow (CBF) autoregulation during
pregnancy/preeclampsia is a major underlying factor. We have compelling data that the ischemic placenta
releases factors into the circulation that can impact cerebral vascular function. These factors include the
cytokine tumor necrosis factor alpha (TNF-α), an activating angiotensin receptor type 1 autoantibody (AT1-
aa), and an increase in soluble fms like tyrosine kinase (sFlt1) that impairs the function of proangiogenic
factors like placental growth factor (PlGF). Importantly, these factors mirror changes that occur in human
preeclampsia and are also observed in our experimental rat model of placental ischemia that mimics the
characteristics of preeclampsia. This grant proposes that TNF-α can impair cerebral vascular tone and
cerebral blood flow autoregulation by regulating intracellular vascular smooth muscle calcium ([Ca2+ ]IC). TNF-α
also stimulates the production of the AT1-aa which is proposed to impair cerebral vascular function through
and angiotensin receptor mediated mechanism. Finally, evidence in the literature shows that either the AT1-
aa or TNF-α can promote an increase in circulating sFlt1 in this model of placental ischemia. sFlt1 has been
shown to increase vascular permeability in the brain, and exogenous administration of the PlGF has been
shown to attenuate hypertension in both rodent and nonhuman primate models of preeclampsia. This proposal
will utilize the rat model of placental ischemia to test the central hypothesis that cerebral complications of
preeclampsia are caused by the release of factors from the ischemic placenta (TNF-α, AT1aa, sFlt1) that
directly impair cerebral vascular tone and blood flow autoregulation. We further hypothesize that these factors
increase BBB permeability, which together with impaired CBF autoregulation leads to cerebral edema. This
hypothesis will be tested in the following aims: (1) To test the hypothesis that circulating TNF-α production
impairs CBF autoregulation by reducing cerebral vascular tone. (2). To test the hypothesis that the AT1-aa
promotes impaired CBF autoregulation during pregnancy through an AT1 receptor mediated mechanism and
directly increases BBB permeability. (3) To test the hypothesis that increased circulating sFlt1 caused by
placental ischemia contributes to cerebral edema by increasing blood brain barrier permeability.

## Key facts

- **NIH application ID:** 9899296
- **Project number:** 5R01HL136684-04
- **Recipient organization:** UNIVERSITY OF MISSISSIPPI MED CTR
- **Principal Investigator:** Heather A Drummond
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $436,757
- **Award type:** 5
- **Project period:** 2017-05-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9899296

## Citation

> US National Institutes of Health, RePORTER application 9899296, Placental Ischemia, Hypertension and Hemodyanmics (5R01HL136684-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9899296. Licensed CC0.

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