# Wnt signaling control of vascular phenotype in obesity

> **NIH NIH R01** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2020 · $635,154

## Abstract

Project Summary/Abstract
 The current proposal represents a combined clinical patient-oriented and experimental murine
investigation which seeks to examine mechanisms of vascular dysfunction in obesity. Obesity has
developed into one of our most critical health care problems as 69% of the US population is currently
overweight or obese. Adipose tissue dysfunction, inflammation, and insulin resistance are essential
hallmarks linking obesity to the pathogenesis of cardiovascular disease. Our preliminary data
demonstrate marked up-regulation of a unique pro-inflammatory Wnt signaling pathway that may play a
major role in mechanisms of vascular dysfunction in obesity. In this proposal, we will examine the role
of Wnt signaling in the regulation of microvascular endothelial function in intact blood vessels and
isolated endothelial cells acquired from living subjects. We will utilize a multidisciplinary approach and
complementary expertise between clinical and basic scientists to characterize the pathophysiological
role of dysfunctional Wnt5a signaling. In aim 1, we will characterize depot-specific mechanisms of
vascular endothelial dysfunction in human adipose tissue arterioles using videomicroscopy of small
vessels isolated from subcutaneous and visceral fat compartments during elective surgical procedures
in 150 obese and 50 age- and gender-matched lean subjects. We will characterize vascular
phenotypes in relation to Wnt signaling and test the hypothesis that over-activation of Wnt5a-mediated
signaling is a dominant regulatory feature that leads to vascular dysfunction. In aims 2 and 3, specific
pharmacological and biological inhibitors of the Wnt5a and TGFβ pathways will be employed using
arterioles and endothelial cells from aim 1 to test the hypothesis that antagonism of Wnt5a reverses
vascular dysfunction, in part through its ability to modulate EndoMT in adipose tissue, and seek to
identify novel regulators and therapeutic targets in obesity. To corroborate these findings in genetic
models, we will explore EndoMT and the vascular and metabolic phenotypes of mice that are
engineered to conditionally ablate or overexpress Wnt5a in myeloid cells. In aim 4, studies of
endothelial phenotyping will be repeated 6-months after life-saving bariatric weight loss surgical
intervention in the same 150 obese subjects from aim 1 to examine the effects of marked weight
reduction on arteriolar responses and relevant Wnt molecular pathways identified in aims 2 and 3. The
overall project combines studies of cellular signaling and whole vessel physiology using primary tissues
from severely obese individuals where clinically very little vascular data currently exist. Our proposal
may identify the Wnt5a-Sfrp5 axis as a novel modulator of vascular biology and potentially lead to the
identification of new targets and approaches to combat obesity-induced cardiovascular disease.

## Key facts

- **NIH application ID:** 9995560
- **Project number:** 5R01HL142650-02
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Noyan Gokce
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $635,154
- **Award type:** 5
- **Project period:** 2019-08-16 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9995560

## Citation

> US National Institutes of Health, RePORTER application 9995560, Wnt signaling control of vascular phenotype in obesity (5R01HL142650-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9995560. Licensed CC0.

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