# PPARG-dependent Mechanisms Control Endothelial-Smooth Muscle Coordination, Arterial Pressure, Vasomotor Function and Arterial Stiffness

> **NIH NIH R35** · MEDICAL COLLEGE OF WISCONSIN · 2020 · $924,000

## Abstract

Summary/Abstract
Blood vessels play an important role in the regulation of arterial blood pressure (BP). Precise BP regulation
requires coordination between vasodilator and vasoconstrictor signals in the endothelium (EC) and smooth
muscle (SMC). EC-derived nitric oxide (NO) is among the key signals which instruct the SMC to dilate or
contract. Our studies show that the NO pathway is coordinately regulated through transcriptional and post-
translational pathways initiated by PPARγ, a nuclear receptor transcription factor. Our data support the
concepts that PPARγ: 1) acts as a sensor in EC to regulate redox state, and through this, bioavailability of NO,
and 2) regulates the responsiveness of SMC to NO by independently controlling a) a RhoA/Rho kinase
(ROCK) activity that promotes constriction, and b) production and stability of cyclic GMP (cGMP), a critical
mediator of vasodilation. The range of PPARγ-dependent molecular mechanisms in both cell types is
surprisingly complex; requiring novel transcriptional co-factors (e.g. retinol binding protein 7; RBP7) which form
a transcriptional regulatory hub with PPARγ, and post-translational regulation of critical SMC mediators (RhoA
and phosphodiesterase 5, PDE5) by Cullin-3 E3 ubiquitin ligase-mediated protein turnover. Importantly, this
PPARγ initiated “final common pathway” has profound effects on vasomotor function, BP and vascular
stiffness, and the studies proposed herein have potential implications for the treatment of these disorders.
However, the signals which initiate and mediate these responses and the range of molecular targets remain
poorly understood. This proposal will focus on two distinct PPARγ-regulated pathways. We will examine the
PPARγ-RhoBTB1-Cullin-3 pathway in smooth muscle and will 1) determine if the RhoBTB1-Cullin-3 pathway
can be exploited as a potential future therapeutic by assessing if RhoBTB1 can protect and reverse
phenotypes in models of hypertension or in other disease models in which vascular dysfunction is a
comorbidity, 2) determine if RhoBTB1 is important in other cells types including endothelium, and 3) employ a
proteomic strategy to identify novel RhoBTB1 binding partners and Cullin-3 substrates in vascular smooth
muscle. We will also examine the PPARγ-RBP7-anti-oxidant pathway in endothelium and will perform 1)
structure function analysis to identify key mechanisms regulating PPARγ transcriptional activity by RBP7, and
2) genome wide transcriptome and chromatin immunoprecipitation studies to assess the contribution of RBP7
to mediated transcriptional activity of PPARγ and its obligate heterodimer RXR. This program will lead to new
concepts and directions of investigation for the field and will not only deepen our understanding of the role of
two fundamentally important pathways in the vasculature, but will also address fundamental transcriptional and
post-translational mechanisms that are of relevance in many cell types.

## Key facts

- **NIH application ID:** 9867744
- **Project number:** 5R35HL144807-02
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Curt Daniel Sigmund
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $924,000
- **Award type:** 5
- **Project period:** 2019-02-06 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9867744

## Citation

> US National Institutes of Health, RePORTER application 9867744, PPARG-dependent Mechanisms Control Endothelial-Smooth Muscle Coordination, Arterial Pressure, Vasomotor Function and Arterial Stiffness (5R35HL144807-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9867744. Licensed CC0.

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