# Pericytes differentiate into smooth muscle cells through HIF2a/SDF1 activation

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2022 · $442,500

## Abstract

ABSTRACT
Pulmonary arterial hypertension (PAH) is a life-threatening disorder characterized by elevated lung pressures,
right heart failure, and premature death. Current therapies fail to prevent disease progression due to their inability
to suppress and/or reverse pulmonary arterial smooth muscle cells (PASMCs) driven muscularization of distal
microvessels. The origin of these highly proliferative PASMCs remains incompletely understood, but may be
closely related to the maladaptive behavior of contiguous pericyte (PC) populations. In addition to providing
mural support to capillaries, PCs can differentiate into other cell types in response to stress. We recently reported
that human PAH lung PCs share lineage markers and functional properties with PASMCs, such as morphology
and contractility. We thus hypothesize that PASMCs in PAH vascular lesions originate from capillary PCs.
Fate-mapping of PCs in chronic hypoxia mice revealed that PCs dissociate from capillaries and relocate to
precapillary arterioles, where they co-express markers of mature SMCs and contribute to muscularization.
Through single cell and bulk RNA-seq analysis, we discovered that the HIF2A/SDF1 signaling pathway is a
master regulator of differentiation of PCs into SMC and a major modifier of PC dysfunction in PAH. We
propose to: 1) demonstrate that HIF2a/SDF1 activation causes PC dissociation from pulmonary capillaries, 2)
define the molecular mechanism by which HIF2a/SDF1 signaling drives PC differentiation into PASMC-like in
human and mice, and 3) determine whether manipulation of HIF2a/SDF1 in PCs can alter the severity of vascular
remodeling in animal models of PH. This project will provide novel insight into pericyte pathobiology and establish
HIF2a/SDF1 as a potential therapeutic target in PAH, for which the first drugs to reverse muscularization and
improve outcomes in PAH may be found.

## Key facts

- **NIH application ID:** 10322180
- **Project number:** 5R01HL150106-02
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Ke Yuan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $442,500
- **Award type:** 5
- **Project period:** 2021-01-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10322180

## Citation

> US National Institutes of Health, RePORTER application 10322180, Pericytes differentiate into smooth muscle cells through HIF2a/SDF1 activation (5R01HL150106-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10322180. Licensed CC0.

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