Abstract
Exogenous vascular endothelial growth factor (VEGF) accelerates compensatory lung growth (CLG) in mice after unilateral pneumonectomy. In this study, we unexpectedly discovered a method to enhance CLG with a VEGF inhibitor, soluble VEGFR1. Eight-week-old C57BL/6 male mice underwent left pneumonectomy, followed by daily intraperitoneal (ip) injection of either saline (control) or 20 μg/kg of VEGFR1-Fc. On post-operative day (POD) 4, mice underwent pulmonary function tests (PFT) and lungs were harvested for volume measurement and analyses of the VEGF signaling pathway. To investigate the role of hypoxia in mediating the effects of VEGFR1, experiments were repeated with concurrent administration of PT-2385, an inhibitor of hypoxia-induced factor (HIF)2α, via orogastric gavage at 10 mg/kg every 12 hours for 4 days. We found that VEGFR1-treated mice had increased total lung capacity (P = 0.006), pulmonary compliance (P = 0.03), and post-euthanasia lung volume (P = 0.049) compared to control mice. VEGFR1 treatment increased pulmonary levels of VEGF (P = 0.008) and VEGFR2 (P = 0.01). It also stimulated endothelial proliferation (P < 0.0001) and enhanced pulmonary surfactant production (P = 0.03). The addition of PT-2385 abolished the increase in lung volume and endothelial proliferation in response to VEGFR1. By paradoxically stimulating angiogenesis and enhancing lung growth, VEGFR1 could represent a new treatment strategy for neonatal lung diseases characterized by dysfunction of the HIF-VEGF pathway.
Highlights
Vascular endothelial growth factor (VEGF) is the cardinal factor of angiogenesis [1]
This paradoxical improvement of compensatory lung growth (CLG) with VEGFR1 at 20 μg/kg remained true on post-operative day (POD) 4 when the lung volume data were pooled from 3 different repetitions under the same experimental condition (59.1 ± 1.3 vs 54.4 ± 1.2 μL/g, P = 0.049) (Fig 1C)
We demonstrated that the administration of VEGFR1-Fc, a VEGF inhibitor, at the dose of 20 μg/kg significantly improved lung volume, surfactant production, angiogenesis, and mechanical properties after left PNX
Summary
Vascular endothelial growth factor (VEGF) is the cardinal factor of angiogenesis [1]. VEGF plays a critical role in pulmonary growth and development [3,4,5]. Signaling from VEGFR2 is critical for physiologic processes such as compensatory lung growth (CLG) [10], and provision of VEGF accelerates alveolar regeneration after unilateral pneumonectomy (PNX) [11]. Targeting the VEGF pathway, can provide a new strategy for improving lung growth and respiratory insufficiency encountered in diseases such as CDH and BPD. We initially aimed to inhibit CLG by using a commercially available VEGF inhibitor, VEGFR1. We aimed to further characterize the physiologic effects of VEGFR1 treatment and the mechanism by which this VEGF inhibitor paradoxically enhanced CLG in the context of hypoxia-induced factor (HIF) regulation
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