# Endothelial-pericyte interactions in the pathogenesis of pulmonary arterial hypertension

> **NIH NIH R01** · STANFORD UNIVERSITY · 2021 · $468,923

## Abstract

Pulmonary arterial hypertension (PAH) is a life-threatening disorder of the pulmonary circulation associated
with loss and impaired regeneration of microvessels. Pericytes are highly specialized cells that interact with
endothelial cells to promote vessel survival but little is known about their role in repair and regeneration of
pulmonary microvessels. One possibility is that failure of pericytes to associate with endothelial cells could
contribute to small vessel loss in PAH by reducing regeneration and viability of pulmonary microvessels.
Using an in vitro co-culture model, we found that pulmonary microvascular endothelial cells (PMVECs) purified
from PAH lungs are unable to recruit healthy lung pericytes; likewise, PAH lung pericytes fail to associate with
healthy PMVECs, suggesting an inherent defect in mechanisms responsible for endothelial-pericyte
interactions. We have discovered that inability of PAH PMVECs to recruit pericytes is associated with reduced
production and release of the Wnt/PCP ligand Wnt5a, since supplementation with recombinant Wnt5a
improves pericyte recruitment and vessel formation. Interestingly, we found that PAH pericytes are resistant to
Wnt5a stimulation, suggesting a possible defect in Wnt/PCP receptor function. Genetic screening led us to
identify ROR2 as a candidate receptor required for Wnt/PCP activation in response to Wnt5a and its loss
prevents pericyte recruitment to healthy microvessels. Therefore, we hypothesize that establishment of
pulmonary endothelial-pericyte interaction is dependent on PMVEC production of Wnt5a, which
attracts pericytes via ROR2 dependent activation of the Wnt/PCP pathway. Through a combination of
novel transgenic animal models, molecular biology and gene editing, we will elucidate for the first time how
Wnt5a and ROR2 orchestrate communication between PMVECs and pericytes (Aims 1 and 2). In addition,
we will also pursue exciting preliminary data that links reduced Wnt5a production in PAH PMVECs to loss of
bone morphogenetic protein (BMP) signaling, a key signaling pathway whose dysregulation is linked to PAH
(Aim 3). Finally, we will demonstrate that PMVEC exosomes are required to deliver Wnt5a to pericytes and
apply a novel technology to isolate and engineer exosomes for in vivo Wnt5a delivery (Aim 4). Understanding
how Wnt5a and ROR2 orchestrate endothelial-pericyte interactions can provide insight into the mechanism
behind progressive small vessel loss in PAH and open new therapeutic opportunities to promote regeneration
of lost vessels, prevent progression and improve clinical outcomes for patients afflicted with this devastating
disease.
!
Pericyte
EC
Proposed model. Pulmonary endothelial cells (ECs) produce and
release Wnt5a in exosomes, which drives pericyte recruitment by
triggering ROR2 phosphorylation (P) and Wnt/PCP activation (top).
Loss of BMPR2 in PAH ECs results in reduced Wnt5a production and
release with consequent reduced Wnt/PCP activation and failure to
establis...

## Key facts

- **NIH application ID:** 10070127
- **Project number:** 5R01HL139664-04
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** VINICIO A DE JESUS PEREZ
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $468,923
- **Award type:** 5
- **Project period:** 2017-12-07 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10070127

## Citation

> US National Institutes of Health, RePORTER application 10070127, Endothelial-pericyte interactions in the pathogenesis of pulmonary arterial hypertension (5R01HL139664-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10070127. Licensed CC0.

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