Evidence map›Paper›PMID 41636059›Full record

ArticleHypertension (Dallas, Tex. : 1979)2026

Loss of ROR2 Tyrosine Kinase Receptor Is Associated With Endothelial Dysfunction in PAH via Inappropriate Integrin β1 Activation.

Ankita Mitra, Stuti Agarwal, Ananya Chakraborty, Brian L Zhong, Lyong Heo, Arpita Roy, Anuradha Bankar, Amanda Pacheco, Natasha Auer, Alexander Dunn and 13 more

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In one paragraph

Article in Hypertension (Dallas, Tex. : 1979), 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

23 authors.

Ankita MitraDivision of Pulmonary and Critical Care (A.M., S.A., A.C., A.R., A.B., A.P., N.A., P.C., A.J., J.A.M.M., E.S.G., V.A.d.J.P.), Stanford University, Palo Alto, CA.ORCID 0000-0002-8425-0933
Stuti AgarwalDivision of Pulmonary and Critical Care (A.M., S.A., A.C., A.R., A.B., A.P., N.A., P.C., A.J., J.A.M.M., E.S.G., V.A.d.J.P.), Stanford University, Palo Alto, CA.ORCID 0000-0002-4436-942X
Ananya ChakrabortyDivision of Pulmonary and Critical Care (A.M., S.A., A.C., A.R., A.B., A.P., N.A., P.C., A.J., J.A.M.M., E.S.G., V.A.d.J.P.), Stanford University, Palo Alto, CA.ORCID 0000-0003-0974-6370
Brian L ZhongDepartment of Chemical Engineering (B.L.Z., A.D.), Stanford University, Palo Alto, CA.
Lyong HeoStanford Center for Genomics and Personalized Medicine, Stanford University School of Medicine (L.H., R.N.).ORCID 0000-0003-4158-9600
Arpita RoyDivision of Pulmonary and Critical Care (A.M., S.A., A.C., A.R., A.B., A.P., N.A., P.C., A.J., J.A.M.M., E.S.G., V.A.d.J.P.), Stanford University, Palo Alto, CA.
Anuradha BankarDivision of Pulmonary and Critical Care (A.M., S.A., A.C., A.R., A.B., A.P., N.A., P.C., A.J., J.A.M.M., E.S.G., V.A.d.J.P.), Stanford University, Palo Alto, CA.ORCID 0009-0005-6864-5379
Amanda PachecoDivision of Pulmonary and Critical Care (A.M., S.A., A.C., A.R., A.B., A.P., N.A., P.C., A.J., J.A.M.M., E.S.G., V.A.d.J.P.), Stanford University, Palo Alto, CA.
Natasha AuerDivision of Pulmonary and Critical Care (A.M., S.A., A.C., A.R., A.B., A.P., N.A., P.C., A.J., J.A.M.M., E.S.G., V.A.d.J.P.), Stanford University, Palo Alto, CA.
Alexander DunnDepartment of Chemical Engineering (B.L.Z., A.D.), Stanford University, Palo Alto, CA.
Prakash ChelladuraiDivision of Pulmonary and Critical Care (A.M., S.A., A.C., A.R., A.B., A.P., N.A., P.C., A.J., J.A.M.M., E.S.G., V.A.d.J.P.), Stanford University, Palo Alto, CA.
Ananya JainDivision of Pulmonary and Critical Care (A.M., S.A., A.C., A.R., A.B., A.P., N.A., P.C., A.J., J.A.M.M., E.S.G., V.A.d.J.P.), Stanford University, Palo Alto, CA.
Juan Andrés Matos MuñozDivision of Pulmonary and Critical Care (A.M., S.A., A.C., A.R., A.B., A.P., N.A., P.C., A.J., J.A.M.M., E.S.G., V.A.d.J.P.), Stanford University, Palo Alto, CA.
Eleana Stephanie GuardadoDivision of Pulmonary and Critical Care (A.M., S.A., A.C., A.R., A.B., A.P., N.A., P.C., A.J., J.A.M.M., E.S.G., V.A.d.J.P.), Stanford University, Palo Alto, CA.
Dan YiDepartment of Internal Medicine, University of Arizona College of Medicine, Phoenix (D.Y., Z.D.).ORCID 0000-0002-2614-5027
Hanqiu ZhaoDivision of Pulmonary and Critical Care and Medicine, Department of Medicine, School of Medicine, Washington University in St. Louis, MO (H.Z., Z.D.).
Kwun Wai Dede ManARTOG Center for Biomedical Engineering Research, University of Bern, Switzerland (K.W.D.M., O.T.G.).
Ramesh NairStanford Center for Genomics and Personalized Medicine, Stanford University School of Medicine (L.H., R.N.).ORCID 0000-0002-1323-3247
Jason HongDivision of Pulmonary and Critical Care, University of California, Los Angeles (UCLA) (J.H.).
Wolfgang M KueblerInstitute of Physiology, Charité-Universitätsmedizin Berlin, Germany (W.M.K.).ORCID 0000-0003-4100-2961
Olivier T GuenatARTOG Center for Biomedical Engineering Research, University of Bern, Switzerland (K.W.D.M., O.T.G.).ORCID 0000-0003-1103-9712
Zhiyu DaiDepartment of Internal Medicine, University of Arizona College of Medicine, Phoenix (D.Y., Z.D.).ORCID 0000-0002-2945-7923
Vinicio A de Jesus PerezDivision of Pulmonary and Critical Care (A.M., S.A., A.C., A.R., A.B., A.P., N.A., P.C., A.J., J.A.M.M., E.S.G., V.A.d.J.P.), Stanford University, Palo Alto, CA.ORCID 0000-0001-5532-8247

Funding

The Wnt7a/ROR2 axis in the pathogenesis of pulmonary arterial hypertensionR01HL134776 · NHLBI · STANFORD UNIVERSITY · PI DE JESUS PEREZ, VINICIO A · 2017 to 2025
$5.0M
Molecular mechanisms underlying force transduction at cellular adhesion complexesR35GM130332 · NIGMS · STANFORD UNIVERSITY · PI Alexander R Dunn · 2019 to 2026
$4.9M
Endothelial-pericyte interactions in the pathogenesis of pulmonary arterial hypertensionR01HL139664 · NHLBI · STANFORD UNIVERSITY · PI DE JESUS PEREZ, VINICIO A · 2018 to 2025
$4.7M
Pericytes and postnatal alveolarization: Role of hypoxia inducible factorsR01HL160018 · NHLBI · STANFORD UNIVERSITY · PI ALVIRA, CRISTINA MARIA, CORNFIELD, DAVID N. · 2022 to 2025
$2.6M
The Role of the CES1 in the Pathogenesis of Pulmonary Arterial HypertensionR01HL172449 · NHLBI · STANFORD UNIVERSITY · PI VINICIO A DE JESUS PEREZ · 2024 to 2026
$1.6M
Integrative Multiomics to Uncover Novel Genes and Networks in Pulmonary Arterial HypertensionK08HL169982 · NHLBI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI Jason Hong · 2023 to 2026
$706k
A novel microfluidic platform to study exosome biology in PAH.R21HL156761 · NHLBI · STANFORD UNIVERSITY · PI DE JESUS PEREZ, VINICIO A, DEMIRCI, UTKAN · 2021 to 2022
$433k
NHLBI NIH HHS K08 HL169982NHLBI NIH HHS R01 HL134776NHLBI NIH HHS R01 HL139664NHLBI NIH HHS R01 HL160018NHLBI NIH HHS R01 HL172449NHLBI NIH HHS R21 HL156761NIGMS NIH HHS R35 GM130332
6 · The paper itself

Abstract

backgroundEndothelial dysfunction is a key feature of pulmonary arterial hypertension (PAH). Previously, we demonstrated decreased Wnt7a transcript levels, causing reduced angiogenesis in PAH. Wnt7a expression correlates with tip formation via ROR2 (receptor tyrosine kinase-like orphan receptor 2), a tyrosine kinase receptor. We hypothesized that ROR2 activation in pulmonary microvascular endothelial cells (PMVECs) promotes angiogenesis, particularly endothelial barrier establishment, and its loss causes PAH.

methodsEndothelial-specific ROR2 knockout (ROR2 ECKO) and wild-type mice were studied under normoxia and chronic hypoxia using echocardiography, hemodynamics, and lung morphometry. PMVECs from healthy and PAH lungs were transfected with ROR2 siRNA/constructs for functional and molecular studies. Focal adhesion activation and force generation were assessed via Förster resonance energy transfer-based methods. Bulk and single-cell transcriptomic analyses were performed on siROR2 (ROR2 siRNA) PMVECs and ROR2 ECKO lungs.

resultsROR2 ECKO mice exacerbated pulmonary hypertension and vascular remodeling in hypoxia. Single-cell RNA-sequencing of lung endothelial cells revealed dysregulated barrier formation and angiogenesis. Evans blue dye extravasation confirmed reduced endothelial barrier integrity in ROR2 ECKO mice. ROR2-deficient PAH PMVECs displayed increased adhesion, permeability, and focal adhesion numbers, with reduced VE-cadherin at cell junctions. Confocal imaging and foster resonance energy transfer revealed ROR2 localization in focal adhesions, interacting with ITGB1 (integrin β1) which remained in an active, adhesion-promoting state in ROR2-deficient cells. Restoring ROR2 in PAH PMVECs normalized adhesion, barrier function, and focal adhesion abundance. Transcriptomic analysis revealed Rab12 mediated ROR2-ITGB1 crosstalk, whose knockdown mimicked ROR2 deficiency in PMVECs.

conclusionsROR2 regulates pulmonary angiogenesis by maintaining endothelial barrier integrity and facilitating integrin recycling. ROR2 restoration could be a potential therapeutic approach for PAH.

Indexed as

Endothelial CellsEndothelium, VascularHypertension, PulmonaryIntegrin beta1Receptor Tyrosine Kinase-like Orphan ReceptorsAnimalsDisease Models, AnimalLungMaleMiceMice, KnockoutVascular RemodelingIntegrin beta1Receptor Tyrosine Kinase-like Orphan ReceptorsRor2 protein, mousecell polarityendothelial cellsfocal adhesionpulmonary arterial hypertensionvascular remodeling

Identifiers

PMID41636059
PMCPMC12959876

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.