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

School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Science, University College Dublin, Belfield, Dublin, Ireland.
Respiratory research (Impact Factor: 3.09). 01/2011; 12(1):17. DOI: 10.1186/1465-9921-12-17
Source: PubMed


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. 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.
Male 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.
Typical 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.
VEGFB 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.

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Available from: Katherine Howell
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    • "However, addition of new blood vessels to the lung as a compensatory mechanism, might be a time-dependent process, as it occurs in the placenta, where distinct factors intervene at different times during gestation (Hamilton et al., 1995; Athanassiades and Lala, 1998; Matsumoto et al., 2002; Wulff et al., 2002), and further studies are needed in this matter. Evidence in this direction was given by Sands et al (2011), as related to the adapting process to hypoxia. They found that the in vivo actions of VEGFB and PGF can either inhibit or potentiate the actions of VEGFA. "

    Full-text · Chapter · Jul 2013
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    • "However, besides VEGF-A also other VEGF family members showed significant mRNA expression increments in resected healthy tissue ranging from 2–3 fold (VEGF-B, VEGF-C, PlGF) up to 22-fold (VEGF-D). Two recent reports described the induction during hypoxia of these VEGF family members in lung and lymphatic endothelial cells [31,32]. It is therefore likely that the combined action of clamping-induced hypoxia and COX2 derived prostaglandins are at the basis of the increased mRNA expression of VEGF-A as well as of the other VEGF family members we observed in resected healthy colon samples. "
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    ABSTRACT: Background mRNA levels of members of the Vascular Endothelial Growth Factor family (VEGF-A, -B, -C, -D, Placental Growth Factor/PlGF) have been investigated as tissue-based markers of colon cancer. These studies, which used specimens obtained by surgical resection or colonoscopic biopsy, yielded contradictory results. We studied the effect of the sampling method on the marker accuracy of VEGF family members. Methods Comparative RT-qPCR analysis was performed on healthy colon and colon carcinoma samples obtained by biopsy (n = 38) or resection (n = 39) to measure mRNA expression levels of individual VEGF family members. mRNA levels of genes encoding the eicosanoid enzymes cyclooxygenase 2 (COX2) and 5-lipoxygenase (5-LOX) and of genes encoding the hypoxia markers glucose transporter 1 (GLUT-1) and carbonic anhydrase IX (CAIX) were included as markers for cellular stress and hypoxia. Results Expression levels of COX2, 5-LOX, GLUT-1 and CAIX revealed the occurrence in healthy colon resection samples of hypoxic cellular stress and a concurrent increment of basal expression levels of VEGF family members. This increment abolished differential expression of VEGF-B and VEGF-C in matched carcinoma resection samples and created a surgery-induced underexpression of VEGF-D. VEGF-A and PlGF showed strong overexpression in carcinoma samples regardless of the sampling method. Conclusions Sampling-induced hypoxia in resection samples but not in biopsy samples affects the marker-reliability of VEGF family members. Therefore, biopsy samples provide a more accurate report on VEGF family mRNA levels. Furthermore, this limited expression analysis proposes VEGF-A and PlGF as reliable, sampling procedure insensitive mRNA-markers for molecular diagnosis of colon cancer.
    Full-text · Article · Nov 2012 · BMC Cancer
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    • "The total length of intra-acinar vessels was unaltered by hypoxia in the mouse. This is somewhat different from our previous findings in the rat, in which we found that intraacinar vessel length increased in response to sustained hypoxia, suggesting new vessel growth (Howell et al. 2003Howell et al. , 2009 Hyvelin et al. 2005; Sands et al. 2011). Nonetheless, vessel loss was not observed in either species and thus could not have contributed to the increased pulmonary vascular resistance of hypoxic pulmonary hypertension. "
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    ABSTRACT: Chronic hypoxic pulmonary hypertension is characterized by a sustained increase in pulmonary arterial pressure due to abnormally elevated pulmonary vascular resistance. This increased vascular resistance was previously thought to be due largely to changes in the structure of the pulmonary vasculature, i.e. lumen narrowing due to wall hypertrophy and loss of vessels. Recently, this model has been challenged by the demonstration that hypoxic pulmonary hypertension in the rat is caused almost completely by sustained vasoconstriction. The contribution of this vasocontriction to hypoxic pulmonary hypertension has not been examined directly in other species. We exposed groups of mice to hypoxia (10% O(2)) or normoxia for 3 weeks, following which the lungs were removed post mortem, and vascular resistance was measured in an isolated, ventilated, perfused preparation. Mean pulmonary vascular resistance was significantly increased in hypoxic compared with control normoxic lungs. The rho kinase inhibitor Y27635 (10(-4)m) (Tocris Bioscience, Bristol, United Kingdom.) significantly reduced the mean (± SEM) hypoxia induced increase by 45.4 (10.8)%, implying that structural vascular changes acounted for the remainder of the hypoxic increase. Stereological quantification showed a significant reduction in the mean lumen diameter of the fully relaxed vessels in hypoxic lungs compared with normoxic control lungs; there was no intra-acinar vessel loss. Thus, in contrast to the rat, hypoxic pulmonary hypertension in the mouse is due to two mechanisms contributing equally: sustained vasoconstriction and structural lumen narrowing of intra-acinar vessels. These important species diferences must be considered when using genetically mutated mice to investigate the mechanisms underlying pulmonary hypertension.
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