Vascular endothelial growth factor contributes to lung vascular hyperpermeability in sepsis-associated acute lung injury

Abstract

Vascular endothelial growth factor (VEGF) is a prime regulator of vascular permeability. Acute lung injury (ALI) is characterized by high-permeability pulmonary edema in addition to refractory hypoxemia and diffuse pulmonary infiltrates. In this study, we examined whether VEGF can be implicated as a pulmonary vascular permeability factor in sepsis-associated ALI. We found that a great increase in lung vascular leak occurred in mice instilled intranasally with lipopolysaccharide (LPS), as assessed by IgM levels in bronchoalveolar lavage fluid. Treatment with the VEGF-neutralizing monoclonal antibody bevacizumab significantly reduced this hyperpermeability response, suggesting active participation of VEGF in non-cardiogenic lung edema associated with LPS-induced ALI. However, this was not solely attributable to excessive levels of intrapulmonary VEGF. Expression levels of VEGF were significantly reduced in lung tissues from mice with both intranasal LPS administration and cecal ligation and puncture (CLP)-induced sepsis, which may stem from decreases in non-endothelial cells-dependent VEGF production in the lungs. In support of this assumption, stimulation with LPS and interferon-γ (IFN-γ) significantly increased VEGF in human pulmonary microvascular endothelial cells (HPMECs) at mRNA and protein levels. Furthermore, a significant rise in plasma VEGF levels was observed in CLP-induced septic mice. The increase in VEGF released from HPMECs after LPS/IFN-γ challenge was completely blocked by either specific inhibitor of mitogen-activated protein kinase (MAPK) subgroups. Taken together, our results indicate that VEGF can contribute to the development of non-cardiogenic lung edema in sepsis-associated ALI due to increased VEGF secretion from pulmonary vascular endothelial cells through multiple MAPK-dependent pathways.

MicroRNA-1 protects the endothelium in acute lung injury

“…Therefore, we tested the status of VEGF and its effect on miR-1 in the injured endothelium. Consistent with previous reports ( 17 , 18 ), treatment with TNF-α or LPS increased VEGF expression in HPMECs ( Figure 3A and Supplemental Figure 1 ; supplemental material available online with this article; https://doi.org/10.1172/jci.insight.164816DS1 ). More importantly, the blockade of VEGF receptor 2 (VEGFR2), the main receptor for VEGF in ECs, completely abrogated miR-1 downregulation, showing the central role of VEGF signaling in miR-1 regulation ( Figure 3B ).…”

“…Furthermore, inhibition of VEGF expression and signaling ameliorates the extent of injury in several models ( 46 , 56 – 58 ). A recent mechanistic study separating the endothelial and nonendothelial fractions of the injured lung concluded that during ALI, VEGF expression in ECs increases, while its expression in non-ECs and the whole lung decreases ( 17 ). The known stimulatory effect of LPS on endothelial VEGF is in line with this observation ( 18 ).…”

Lipopolysaccharide-induced murine lung injury results in long-term pulmonary changes and downregulation of angiogenic pathways

“…Prior studies suggest that VEGF may have a pathological role in ALI/ARDS in the short-term by contributing to increased permeability of the capillary membrane leading to noncardiogenic pulmonary edema 32 . However, other studies have found that VEGF may function through autocrine signaling as a pneumotrophic factor in the lung, facilitating recovery from lung injury in the long-term 11,[33][34][35][36] .…”

Targeting the lung endothelial niche to promote angiogenesis and regeneration: A review of applications

“…VEGF has been evaluated in animal ALI models but the data regarding its role as a therapeutic agent have been conflicting ( Medford and Millar, 2006 ). In the short-term, VEGF may have pathologic effects by increasing alveolar-capillary membrane permeability within the EC niche and contributing to exudate formation ( Tomita et al, 2020 ). For example, SU5416, a potent and selective VEGFR2 inhibitor, ameliorated epithelial cell injury and histopathological changes in a murine ALI model following lipopolysaccharide (LPS) administration ( Huang et al, 2019 ).…”