# Function and Regulation of TSPAN2 in Vascular Disease

> **NIH NIH R01** · AUGUSTA UNIVERSITY · 2020 · $522,237

## Abstract

PROJECT SUMMARY
Differentiated vascular smooth muscle cells (VSMCs) are genetically programmed to proliferate and migrate at
low rate while carrying out contractility for adult vessel homeostasis. VSMCs are not terminally differentiated
and can undergo phenotypic switching to a dedifferentiated synthetic mode in response to various
pathophysiological stimuli, contributing to diverse vascular diseases such as atherosclerosis and restenosis.
Due to cell surface accessibility, cell membrane regulators required for VSMC differentiation may hold
attractive therapeutic potential. However, there is a paucity of information on key transmembrane regulators
governing VSMC differentiation. TSPANs possess a unique signaling platform, termed as tetraspanin-enriched
microdomains (TEMs) organized in cis with TSPANs and other transmembrane partners including receptor
tyrosine kinases and integrin(s). TSPANs serve as membrane “docking” molecules, exerting critical roles in
diverse signal cascades. Recent genome wide association studies have specifically linked TSPAN2 to
atherosclerosis and blood pressure control. Inspired by these findings, we interrogated data from multiple RNA
screenings and consistently found that TSPAN2 is the sole TSPANs member significantly decreased during
VSMC phenotypic modulation and in diseased vessels. TSPAN2 is enriched in VSMCs and exhibits serum
response factor (SRF) /Myocardin (MYOCD)-dependent expression in vitro. New functional data shows that
depletion of TSPAN2 in VSMCs attenuates contractile gene expression, while promoting VSMC proliferation
and migration; forced expression of TSPAN2 blocks neointima formation in a balloon injury model. TSPAN2
interacts with and promotes degradation of CD44 protein, a prominent pathological mediator in vascular
disease. In addition, TSPAN2 interacts with the laminin-binding integrin α3β1, and β1 integrins are essential to
the maintenance of the VSMC contractile phenotype. These preliminary findings support a novel hypothesis
that TSPAN2 stabilizes the VSMC contractile phenotype and suppresses vascular pathology via two distinct
pathways: by promoting degradation of CD44 protein which inactivates the synthetic VSMC phenotype and
interaction with integrin α3β1 which facilitates the contractile phenotype. Three specific aims are proposed to
test this hypothesis. Aim 1 will determine functions of TSPAN2 in arteriovenous fistula and atherosclerosis
mouse models. Aim 2 will elucidate the mechanisms through which TSPAN2 stabilizes the VSMC contractile
phenotype involving inactivation of the synthetic VSMC phenotype by promoting CD44 protein degradation and
activation of the contractile phenotype by interacting with integrin α3β1. Aim 3 will elucidate the molecular
basis for the impaired TSPAN2 gene expression under pathological vascular conditions via perturbation of
SRF/MYOCD pathway. Successful completion of this proposal will reveal previously unknown molecular
mechanisms governing VSMC phenotyp...

## Key facts

- **NIH application ID:** 10083017
- **Project number:** 7R01HL139794-02
- **Recipient organization:** AUGUSTA UNIVERSITY
- **Principal Investigator:** Xiaochun Long
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $522,237
- **Award type:** 7
- **Project period:** 2020-01-08 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10083017

## Citation

> US National Institutes of Health, RePORTER application 10083017, Function and Regulation of TSPAN2 in Vascular Disease (7R01HL139794-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10083017. Licensed CC0.

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