Verlies van ROR2-tyrosinekinase veroorzaakt endotheeldisfunctie bij PAH

BACKGROUND:Endothelial 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.METHODS:Endothelial-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 (RO