# The Wnt7a/ROR2 axis in the pathogenesis of pulmonary arterial hypertension

> **NIH NIH R01** · STANFORD UNIVERSITY · 2024 · $116,227

## Abstract

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by abnormally elevated
pulmonary pressures and right ventricular (RV) failure. Inappropriate angiogenesis is a key pathological feature
of PAH associated with endothelial dysfunction and progressive loss of pulmonary and RV microvessels.
Angiogenesis is the process by which new vessels arise from existing vessels and is mainly driven by VEGF
signaling. In response to VEGF-A, endothelial cells differentiate into tip cells, highly motile cells that direct vessel
sprouting and elongation. Our previous R01 was built on the hypothesis that tip cell formation by PMVECs
requires crosstalk between the VEGF and the Wnt/planar cell polarity (Wnt/PCP), a pathway responsible for
coordinating cell movements during tissue morphogenesis. We demonstrated that Wnt/PCP activation in
PMVECs is driven by the interaction between the ligand Wnt7a and ROR2, a tyrosine kinase receptor that
phosphorylates residues in the endothelial VEGFR2 cytoplasmic domain to augment VEGF signaling output.
We found that, compared to healthy donors, tip cell formation and angiogenesis in response to VEGF-A was
significantly reduced in pulmonary microvascular endothelial cells (PMVEC) from PAH patients. Most
importantly, supplementation with recombinant Wnt7a or restoration of ROR2 expression in PAH PMVECs
results in recovery of the VEGF-A response, leading us to conclude that Wnt7a/ROR2 signaling is required for
appropriate VEGF signaling activation and angiogenic response in PMVECs.
This renewal will focus on elucidating the transcriptional and epigenetic mechanisms that regulate Wnt7a/ROR2
expression in healthy and PAH PMVECs (Aim 1), how interaction between ROR2 and integrins is required to
establish a functional lung endothelial barrier (Aim 2), and the critical role of Wnt7a/ROR2 as a key pro-
angiogenic mechanism that supports compensatory angiogenesis during RV adaptation to PAH (Aim 3). The
studies in this renewal will confirm the role of Wnt7a/ROR2 signaling as a master regulator of
cardiopulmonary angiogenesis and demonstrate the therapeutic potential of restoring Wnt7a/ROR2
signaling to prevent small vessel loss and improve RV function in PAH.

## Key facts

- **NIH application ID:** 11050455
- **Project number:** 3R01HL134776-08S1
- **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:** $116,227
- **Award type:** 3
- **Project period:** 2017-02-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11050455

## Citation

> US National Institutes of Health, RePORTER application 11050455, The Wnt7a/ROR2 axis in the pathogenesis of pulmonary arterial hypertension (3R01HL134776-08S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/11050455. Licensed CC0.

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