Unveiling the impact of VEGFR2/KDR modulation on pulmonary microvascular endothelial cells in COPD/emphysema

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Background: Chronic Obstructive Pulmonary Disease (COPD) poses a global vascular challenge in emphysema. As VEGFR2/KDR is a shear stress sensor and pivotal for maintaining vascular integrity, we examined its role in sustaining pulmonary microvascular endothelial barrier integrity. Methods: VEGFR2/KDR expression was assessed in pulmonary microvascular endothelial cells (MVECs) from COPD/emphysema patients and mice exposed to prolonged smoking. MVECs underwent shear stress, with VEGFR2 expression and signaling modified via short hairpin KDR and inhibitors of VEGFR2, ERK, and Akt. We evaluated cell alignment, elongation, gap size, and activation of pY1175-VEGFR2/ERK and pY951-VEGFR2/Akt pathways via RNA sequencing, qPCR, and confocal microscopy. Results: VEGFR2/KDR was reduced in MVECs from COPD/emphysema patients and mice exposed to prolonged smoking. Shear stress enhanced VEGFR2/KDR expression and activated pY1175-VEGFR2-ERK. VEGFR2 blockade altered alignment and increased gaps, while ERK inhibition induced apoptosis and disrupted morphology. RNA sequencing after shear stress revealed a blunted integrin β3 response in shKDR-treated cells. Conclusions: VEGFR2 signaling via pY1175-VEGFR2/ERK is crucial for endothelial integrity, affecting cell morphology and barrier function through integrin β3, underscoring VEGFR2's significance in MVEC structure and pointing to its therapeutic potential in COPD/emphysema. erj;66/suppl_69/PA1025/F1 F1 F1

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