# Molecular Mechanisms of 20-HETE-mediated Vascular Dysfunction and Hypertension

> **NIH NIH R01** · NEW YORK MEDICAL COLLEGE · 2020 · $687,846

## Abstract

SUMMARY
This proposal seeks to test the hypothesis that the specific activation of the G-protein-coupled receptor GPR75
(Gq) in the endothelium and vascular smooth muscle is central to the mechanisms underlying 20-HETE-
dependent vascular dysfunction and hypertension. The foundation for this hypothesis stems from studies
implicating the cytochrome P450 (CYP) 4-derived 20-HETE in setting the level of systemic arterial blood
pressure (BP), in human subjects and experimental animals, via actions on vascular and renal structures. We
demonstrated that pharmacological and genetic interventions that increase synthesis of 20-HETE in rodents
also cause elevation of BP. Conversely, the BP of hypertensive rodents, featuring increased 20-HETE
synthesis, was diminished by pharmacological or genetic manipulations that interfere with the synthesis or the
action of this eicosanoid, thus providing compelling evidence that 20-HETE contributes importantly to pro-
hypertensive mechanisms. Previous and preliminary studies, have shown that conditional overexpression of
Cyp4a12 (the murine 20-HETE synthase) selectively in endothelial cells (EC) or vascular smooth muscle cells
(VSMC) prompts development of hypertension in mice, raising the intriguing possibility that the mechanism(s)
underlying 20-HETE-induced hypertension vary with cell type targeted by this eicosanoid. It also raises the
possibility of the presence of a common target/receptor that governs distinct cell-specific 20-HETE-triggered
signaling pathways leading to complex functional outcomes, including endothelial dysfunction, ACE
induction/RAS activation, inflammation, smooth muscle contraction and vascular remodeling; all of which
contribute to BP regulation. In this regard, we have exciting preliminary data demonstrating the identification of
a G-protein coupled receptor (GPCR), GPR75 (Gq), an orphan GPCR, as the putative 20-HETE receptor. We
show that: 1) 20-HETE specifically binds to EC membranes and this binding is negated in GPR75-deficient
membranes; 2) 20-HETE stimulates GPR75-Gαq/11 dissociation in EC and VSMC and intracellular i[Ca2+]
accumulation in EC; 3) GPR75 knockdown negates 20-HETE-stimulated EGFR phosphorylation, the initial
signaling step of 20-HETE in EC; 4) GPR75 is expressed in tissues where 20-HETE exerts its actions (EC,
VSMC, renal arteries and kidney); and 5) In vivo knockdown of GPR75 prevents DOX-induced 20-HETE-driven
BP elevation, endothelial dysfunction, smooth muscle contractility and vascular remodeling in Cyp4a12tg mice.
Accordingly, we postulate that 20-HETE binds to GPR75 and triggers cell-specific signal transduction
pathways leading to endothelial dysfunction, ACE upregulation, smooth muscle contractility and
vascular remodeling, all of which contribute to hypertension We propose four aims that systematically
determine the proximal signaling of GPR75-20-HETE pairing in EC and VSMC and assess the importance of
GPR75 activation to the hypertension driven by increased 20-...

## Key facts

- **NIH application ID:** 9834969
- **Project number:** 5R01HL139793-03
- **Recipient organization:** NEW YORK MEDICAL COLLEGE
- **Principal Investigator:** Michal Laniado Schwartzman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $687,846
- **Award type:** 5
- **Project period:** 2017-12-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9834969

## Citation

> US National Institutes of Health, RePORTER application 9834969, Molecular Mechanisms of 20-HETE-mediated Vascular Dysfunction and Hypertension (5R01HL139793-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9834969. Licensed CC0.

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