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

> **NIH NIH R01** · STANFORD UNIVERSITY · 2024 · $691,933

## Abstract

Pulmonary arterial hypertension (PAH) is a life-threatening disorder characterized by elevated pulmonary
pressures and right heart failure. A hallmark of PAH pathology is progressive loss and inappropriate regeneration
of pulmonary and right ventricular (RV) microvessels. Pericytes are highly specialized mural cells that interact
with endothelial cells to provide structural support and facilitate vessel maturation during angiogenesis. Our
studies show that inability to establish proper endothelial-pericyte (EC-PC) interactions is associated with
pulmonary small vessel loss and insufficient angiogenesis in PAH, leading us to speculate that targeting the
mechanisms that orchestrate EC-PC interactions could open new therapeutic opportunities for PAH. We have
demonstrated that dysfunctional Wnt/planar cell polarity (PCP) signaling contributes to small vessel loss in PAH
by disrupting lung EC-PC interactions. We found that pulmonary microvascular endothelial cells (PMVECs)
release Wnt5a to recruit lung pericytes via ROR2-dependent Wnt/PCP activation in pericytes. Compared to
healthy donors, both Wnt5a production and ROR2-dependent Wnt/PCP activation are significantly reduced in
PAH PMVECs and pericytes, respectively. We also found that endothelial-specific Wnt5a deletion in mice was
associated with decompensated RV failure characterized by disrupted EC-PC interactions and reduced RV
capillary density. Based on our findings, we hypothesize that loss of Wnt/PCP signaling contributes to lung
and RV vessel dysfunction in PAH by disrupting the establishment of EC-PC interactions and
angiogenesis. In this renewal, we plan to: (Aim 1) Elucidate the mechanisms responsible for inappropriate
Wnt5a expression by PAH PMVECs, (Aim 2) Elucidate the mechanisms responsible for dysfunctional ROR2
activity in PAH pericytes, and (Aim 3) Demonstrate that Wnt5a/ROR2 signaling plays a key role in RV remodeling
and angiogenesis in response to PAH. Understanding how Wnt/PCP orchestrates endothelial-pericyte
interactions will provide insight into the PAH pathogenesis and open new therapeutic opportunities to promote
regeneration of lost vessels, prevent progression and improve clinical outcomes for patients afflicted with this
devastating disease.

## Key facts

- **NIH application ID:** 10900789
- **Project number:** 5R01HL139664-07
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** VINICIO A DE JESUS PEREZ
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $691,933
- **Award type:** 5
- **Project period:** 2017-12-07 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10900789

## Citation

> US National Institutes of Health, RePORTER application 10900789, Endothelial-pericyte interactions in the pathogenesis of pulmonary arterial hypertension (5R01HL139664-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10900789. Licensed CC0.

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