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Genetic variation in vascular endothelial growth factor-a and lung function.

ABSTRACT: Given the role of vascular endothelial growth factor (VEGF) in lung development, we hypothesized that polymorphisms in VEGF-A may be associated with lung function.The current study was designed to assess the role of genetic variants in VEGF-A as determinants of airway function from infancy through early adulthood.Association between five single-nucleotide polymorphisms (SNPs) in VEGF-A and lung function were assessed longitudinally in two unselected birth cohorts and cross-sectionally among infants. Replication with two SNPs was conducted in adults and children with asthma. We investigated the functionality of the SNP most consistently associated with lung function (rs3025028) using Western blotting to measure the ratio of plasma VEGF-A(165b)/panVEGF-A(165) among homozygotes.In two populations in infancy, C-allele homozygotes of rs3025028 had significantly higher VmaxFRC, forced expiratory flow(50), and forced expiratory flow(25-75) compared with other genotype groups. Among preschool children (age 3 yr), C allele of rs3025028 was associated with significantly higher specific airway conductance, with similar findings observed for lung function in school-age children. For FEV(1)/FVC ratio similar findings were observed among adolescents and young adults (birth cohort), and then replicated in adults and schoolchildren with asthma (cross-sectional studies). For rs3025038, plasma VEGF-A(165b)/panVEGF-A(165) was significantly higher among CC versus GG homozygotes (P ? 0.02) at birth, in school-age children, and in adults.We report significant associations between VEGF-A SNP rs3025028 and parameters of airway function measured throughout childhood, with the effect persisting into adulthood. We propose that the mechanism may be mediated through the ratios of active and inhibitory isoforms of VEGF-A(165), which may be determined by alternative splicing.

SUBMITTER: Simpson A

PROVIDER: S-EPMC3373065 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Genetic variation in vascular endothelial growth factor-a and lung function.

Simpson Angela A Custovic Adnan A Tepper Robert R Graves Penelope P Stern Debra A DA Jones Marcus M Hankinson Jenny J Curtin John A JA Wu Jiakai J Blekic Mario M Bukvic Blazenka Kljaic BK Aberle Neda N Marinho Susana S Belgrave Danielle D Morgan Wayne J WJ Martinez Fernando D FD

American journal of respiratory and critical care medicine 20120329 11

<h4>Rationale</h4>Given the role of vascular endothelial growth factor (VEGF) in lung development, we hypothesized that polymorphisms in VEGF-A may be associated with lung function.<h4>Objectives</h4>The current study was designed to assess the role of genetic variants in VEGF-A as determinants of airway function from infancy through early adulthood.<h4>Methods</h4>Association between five single-nucleotide polymorphisms (SNPs) in VEGF-A and lung function were assessed longitudinally in two unse ...[more]

PMID: 22461367

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Project description:BackgroundReceptor signaling is central to vascular endothelial function and is dysregulated in vascular diseases such as atherosclerosis and pulmonary arterial hypertension (PAH). Signaling pathways involved in endothelial function include vascular endothelial growth factor receptors (VEGFRs) and G protein-coupled receptors, which classically activate distinct intracellular signaling pathways and responses. The mechanisms that regulate these signaling pathways have not been fully elucidated and it is unclear what nodes for cross talk exist between these diverse signaling pathways. For example, multifunctional β-arrestin (ARRB) adapter proteins are best known as regulators of G protein-coupled receptor signaling, but their role at other receptors and their physiological importance in the setting of vascular disease are unclear.MethodsWe used a combination of human samples from PAH, human microvascular endothelial cells from lung, and Arrb knockout mice to determine the role of ARRB1 in endothelial VEGFR3 signaling. In addition, a number of biochemical analyses were performed to determine the interaction between ARRB1 and VEGFR3, signaling mediators downstream of VEGFR3, and the internalization of VEGFR3.ResultsExpression of ARRB1 and VEGFR3 was reduced in human PAH, and the deletion of Arrb1 in mice exposed to hypoxia led to worse PAH with a loss of VEGFR3 signaling. Knockdown of ARRB1 inhibited VEGF-C-induced endothelial cell proliferation, migration, and tube formation, along with reduced VEGFR3, Akt, and endothelial nitric oxide synthase phosphorylation. This regulation was mediated by direct ARRB1 binding to the VEGFR3 kinase domain and resulted in decreased VEGFR3 internalization.ConclusionsOur results demonstrate a novel role for ARRB1 in VEGFR regulation and suggest a mechanism for cross talk between G protein-coupled receptors and VEGFRs in PAH. These findings also suggest that strategies to promote ARRB1-mediated VEGFR3 signaling could be useful in the treatment of pulmonary hypertension and other vascular disease.

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Genetic variation in vascular endothelial growth factor-a and lung function.

Publications

Genetic variation in vascular endothelial growth factor-a and lung function.

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