Placenta growth factor and vascular endothelial growth factor B expression in the hypoxic lung

Michelle Sands,Katherine Howell,Paul Mcloughlin,Christine M Costello

doi:10.1186/1465-9921-12-17

Abstract

BackgroundChronic alveolar hypoxia, due to residence at high altitude or chronic obstructive lung diseases, leads to pulmonary hypertension, which may be further complicated by right heart failure, increasing morbidity and mortality. In the non-diseased lung, angiogenesis occurs in chronic hypoxia and may act in a protective, adaptive manner. To date, little is known about the behaviour of individual vascular endothelial growth factor (VEGF) family ligands in hypoxia-induced pulmonary angiogenesis. The aim of this study was to examine the expression of placenta growth factor (PlGF) and VEGFB during the development of hypoxic pulmonary angiogenesis and their functional effects on the pulmonary endothelium.MethodsMale Sprague Dawley rats were exposed to conditions of normoxia (21% O2) or hypoxia (10% O2) for 1-21 days. Stereological analysis of vascular structure, real-time PCR analysis of vascular endothelial growth factor A (VEGFA), VEGFB, placenta growth factor (PlGF), VEGF receptor 1 (VEGFR1) and VEGFR2, immunohistochemistry and western blots were completed. The effects of VEGF ligands on human pulmonary microvascular endothelial cells were determined using a wound-healing assay.ResultsTypical vascular remodelling and angiogenesis were observed in the hypoxic lung. PlGF and VEGFB mRNA expression were significantly increased in the hypoxic lung. Immunohistochemical analysis showed reduced expression of VEGFB protein in hypoxia although PlGF protein was unchanged. The expression of VEGFA mRNA and protein was unchanged. In vitro PlGF at high concentration mimicked the wound-healing actions of VEGFA on pulmonary microvascular endothelial monolayers. Low concentrations of PlGF potentiated the wound-healing actions of VEGFA while higher concentrations of PlGF were without this effect. VEGFB inhibited the wound-healing actions of VEGFA while VEGFB and PlGF together were mutually antagonistic.ConclusionsVEGFB and PlGF can either inhibit or potentiate the actions of VEGFA, depending on their relative concentrations, which change in the hypoxic lung. Thus their actions in vivo depend on their specific concentrations within the microenvironment of the alveolar wall during the course of adaptation to pulmonary hypoxia.

Highlights

Chronic alveolar hypoxia, due to residence at high altitude or chronic obstructive lung diseases, leads to pulmonary hypertension, which may be further complicated by right heart failure, increasing morbidity and mortality
The ratio of right ventricular free wall (RV) to LV+S weight was observed to increase at 14 days of hypoxia relative to matched control values indicating that prolonged chronic hypoxia produced significant RV hypertrophy
Excess placenta growth factor (PlGF) expression in the lung of the transgenic mouse could cause a loss of synergism between PlGF and vascular endothelial growth factor A (VEGFA), similar to that demonstrated here in vitro, resulting in decreased VEGFA activity. These findings suggest that the increased PlGF expression observed in the serum and BAL fluid of chronic obstructive pulmonary disease (COPD) patients could contribute to the progression of emphysema and COPD [21]

Summary

Introduction

Due to residence at high altitude or chronic obstructive lung diseases, leads to pulmonary hypertension, which may be further complicated by right heart failure, increasing morbidity and mortality. Pulmonary hypertension frequently occurs in people suffering from hypoxic lung diseases such as chronic obstructive pulmonary disease (COPD), emphysema, cystic fibrosis and fibrosing alveolitis, often resulting in right heart failure and increased morbidity and mortality [1,2,3]. Such diseases cause tissue destruction within the airways and gas exchange regions of the lung, accompanied by a loss of the pulmonary vasculature (rarefaction). The mechanisms underlying this are poorly understood but are of interest given the therapeutic potential in diseases that are characterised by vessel loss; e.g. idiopathic pulmonary fibrosis, pulmonary arterial hypertension and emphysema

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