A paradoxical method to enhance compensatory lung growth: Utilizing a VEGF inhibitor

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.

Association of Maternal Preeclampsia with Neonatal Respiratory Distress Syndrome in Very-Low-Birth-Weight Infants

“…Preeclampsia is characterized by an imbalanced maternal angiogenic state, resulting in generalized endothelial dysfunction, increased levels of maternal antiangiogenic factor soluble fms-like tyrosine kinase-1 (sFlt-1), and decreased free circulating levels of the angiogenic factors vascular endothelial growth factor (VEGF) and placental growth factor 20–23 . VEGF is important for normal lung vasculature 24 and surfactant protein production 25–27 . sFlt-1, an antagonist of VEGF, can impede VEGF signaling and lead to impaired surfactant production.…”

Drug Regimen for Patients after a Pneumonectomy

“…As these patients are susceptible to postoperative complications and respiratory failure, conservative management of the remaining lung may not be adequate to improve quality of life. Present studies have been aiming to develop treatments that can actively improve pulmonary function after a pneumonectomy [113][114][115][116][117][118][119][120][121][122][123][124][125]. Among these studies, post-pneumonectomy compensatory lung growth seems to be especially promising.…”

“…There are two novel methods that potentially stimulate compensatory lung growth after a pneumonectomy: the administration of VEGF receptor 1 (VEGFR1) and erythropoietin (EPO). A recent study reported that the systemic administration of VEGFR1, a VEGF inhibitor, stimulated angiogenesis and increased lung volume of mice [120]. VEGFR1 increased the level of VEGF and VEGFR2 in the lung, enhancing endothelial proliferation and pulmonary surfactant production [120].…”

“…A recent study reported that the systemic administration of VEGFR1, a VEGF inhibitor, stimulated angiogenesis and increased lung volume of mice [120]. VEGFR1 increased the level of VEGF and VEGFR2 in the lung, enhancing endothelial proliferation and pulmonary surfactant production [120]. Although it cannot be easily applied to humans, VEGFR1 was effective in stimulating compensatory lung growth in mice at the dose of 20 µg/kg [120].…”

“…VEGFR1 increased the level of VEGF and VEGFR2 in the lung, enhancing endothelial proliferation and pulmonary surfactant production [120]. Although it cannot be easily applied to humans, VEGFR1 was effective in stimulating compensatory lung growth in mice at the dose of 20 µg/kg [120]. Meanwhile, EPO was also found to promote endothelial cells growth and to induce angiogenesis [121].…”