Sequestration of Vascular Endothelial Growth Factor (VEGF) Induces Late Restrictive Lung Disease

Abstract

RationaleNeonatal respiratory distress syndrome is a restrictive lung disease characterized by surfactant deficiency. Decreased vascular endothelial growth factor (VEGF), which demonstrates important roles in angiogenesis and vasculogenesis, has been implicated in the pathogenesis of restrictive lung diseases. Current animal models investigating VEGF in the etiology and outcomes of RDS require premature delivery, hypoxia, anatomically or temporally limited inhibition, or other supplemental interventions. Consequently, little is known about the isolated effects of chronic VEGF inhibition, started at birth, on subsequent developing lung structure and function.ObjectivesTo determine whether inducible, mesenchyme-specific VEGF inhibition in the neonatal mouse lung results in long-term modulation of AECII and whole lung function.MethodsTriple transgenic mice expressing the soluble VEGF receptor sFlt-1 specifically in the mesenchyme (Dermo-1/rtTA/sFlt-1) were generated and compared to littermate controls at 3 months to determine the impact of neonatal downregulation of mesenchymal VEGF expression on lung structure, cell composition and function. Reduced tissue VEGF bioavailability has previously been demonstrated with this model.Measurements and Main ResultsTriple transgenic mice demonstrated restrictive lung pathology. No differences in gross vascular development or protein levels of vascular endothelial markers was noted, but there was a significant decrease in perivascular smooth muscle and type I collagen. Mutants had decreased expression levels of surfactant protein C and hypoxia inducible factor 1-alpha without a difference in number of type II pneumocytes.ConclusionsThese data show that mesenchyme-specific inhibition of VEGF in neonatal mice results in late restrictive disease, making this transgenic mouse a novel model for future investigations on the consequences of neonatal RDS and potential interventions.

Poly-lactic acid nanoparticles (PLA-NP) promote physiological modifications in lung epithelial cells and are internalized by clathrin-coated pits and lipid rafts

“…Regarding VEGF, it is involved with angiogenesis, growth and proliferation of lung epithelial cells through autocrine mechanisms, as well as in tissue repair and survival [ 27 , 30 , 48 ]. In addition, reduced levels of VEGF result in increased markers of oxidative stress and structural alterations of alveoli [ 72 ], being implicated in the pathogenesis of restrictive and obstructive lung diseases such as emphysema [ 74 ]. Nevertheless, it is conceivable that the transient reduction of IL-12 and VEGF levels induced by PLA-NP may not impact on lung epithelial cell function.…”

Consequences of a Maternal High-Fat Diet and Late Gestation Diabetes on the Developing Rat Lung

“…Congruently, diabetes-exposed and HF diet-exposed offspring had lower lung expression of VEGF and its redox-sensitive scaffolding protein Txnip, which is necessary for sustained signaling for endothelial cell proliferation, migration, tube formation and vessel growth [ 35 , 46 ]. Interestingly, previous studies have demonstrated late restrictive lung disease with VEGF inhibition [ 47 ]. In sum, our findings suggest multiple mechanisms that could lead to pulmonary vascular maladaptation and maldevelopment leading to PPHN at birth and functional lung disease over time in exposed offspring.…”

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“…48 Lack of ability to undergo apoptosis is the major cause of both tumorigenesis and tumor growth. 49 There are three well-known pro-apoptotic pathways, including the death receptor, mitochondrial, and endoplasmic reticulum enzyme pathway. The B-cell lymphoma 2 (Bcl-2) groups play a major role in the regulation of the mitochondrial pathway.…”