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Loss of ROR2 Tyrosine Kinase Receptor Is Associated With Endothelial Dysfunction in PAH via Inappropriate Integrin β1
Ankita Mitra1, Stuti Agarwal1, Ananya Chakraborty1
1Division 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.
Hypertension (Dallas, Tex. : 1979)
|February 4, 2026
Summary
Loss of receptor tyrosine kinase-like orphan receptor 2 (ROR2) worsens pulmonary arterial hypertension by impairing endothelial barrier integrity. Restoring ROR2 function may offer a new therapeutic strategy for PAH.
Area of Science:
- Cardiovascular Research
- Pulmonary Medicine
- Cell Biology
Background:
- Endothelial dysfunction is a hallmark of pulmonary arterial hypertension (PAH).
- Previous research linked decreased Wnt7a transcript levels to reduced angiogenesis in PAH.
- Wnt7a expression correlates with tip formation via receptor tyrosine kinase-like orphan receptor 2 (ROR2).
Purpose of the Study:
- To investigate the role of ROR2 activation in pulmonary microvascular endothelial cells (PMVECs).
- To determine if ROR2 promotes angiogenesis and endothelial barrier establishment.
- To test the hypothesis that ROR2 loss contributes to PAH.
Main Methods:
- Studied endothelial-specific ROR2 knockout (ROR2 ECKO) and wild-type mice under normoxia and hypoxia.
- Utilized echocardiography, hemodynamics, and lung morphometry.
- Performed functional and molecular studies on PMVECs using ROR2 siRNA/constructs and transcriptomic analyses.
Main Results:
- ROR2 ECKO mice showed exacerbated pulmonary hypertension and vascular remodeling.
- Single-cell RNA-sequencing revealed dysregulated barrier formation and angiogenesis in ROR2 ECKO lungs.
- ROR2 deficiency in PAH PMVECs increased adhesion and permeability, with ROR2 interacting with integrin β1 (ITGB1) in focal adhesions.
Conclusions:
- ROR2 is crucial for pulmonary angiogenesis by maintaining endothelial barrier integrity and facilitating integrin recycling.
- ROR2-ITGB1 crosstalk, mediated by Rab12, is a key pathway.
- ROR2 restoration presents a potential therapeutic avenue for PAH.
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