Expression of Vascular Endothelial Growth Factor and Flk-1 in Developing and Glucocorticoid-Treated Mouse Lung

Abstract

Although the endothelial cell is the most abundant cell type in the differentiated lung, little is known about regulation of lung developmental vasculogenesis. Vascular endothelial growth factor (VEGF) is an endothelial cell mitogen and angiogenic factor that has putative roles in vascular development. Mitogenic actions of VEGF are mediated by the tyrosine kinase receptor KDR/murine homologue fetal liver kinase Flk-1. HLF (hypoxia-inducible factor-like factor) is a transcription factor that increases VEGF gene transcription. Dexamethasone augments lung maturation in fetal and postnatal animals. However, in vitro studies suggest that dexamethasone blocks induction of VEGF. The objectives for the current study were to measure VEGF mRNA and Flk-1 mRNA in developing mouse lung and to measure the effects of dexamethasone treatment in vivo on VEGF and Flk-1 in newborn mouse lung. Our results show that VEGF and Flk-1 messages increase in parallel during normal lung development (d 13 embryonic to adult) and that the distal epithelium expresses VEGF mRNA at all ages examined. Dexamethasone (0.1-5.0 mg x kg(-1) x d(-1)) treatment of 6-d-old mice resulted in significantly increased VEGF, HLF, and Flk-1 mRNA. Dexamethasone did not affect cell-specific expression of VEGF, VEGF protein, or proportions of VEGF mRNA splice variants. These data suggest that the developing alveolar epithelium has an important role in regulating alveolar capillary development. In addition, unlike effects on cultured cells, dexamethasone, even in relatively high doses, did not adversely affect VEGF expression in vivo. The relatively high levels of VEGF and Flk-1 mRNA in adult lung imply a role for pulmonary VEGF in endothelial cell maintenance or capillary permeability.

Traqueo-oclusão intra-útero: técnica cirúrgica associada à corticoterapia promove aumento nos receptores de VEGF (Vascular Endothelial Growth Factor) em pulmões de fetos de ratas

“…Os glicocorticóides alteram a expressão do VEGF e do receptor Flk-1 no período pós-natal em pulmões de fetos normais sendo que in vivo a Dex estimula a produção de ambos e in vitro há supressão dos mesmos com Dex. Nessa fase de maturação, a proliferação endotelial é baixa sugerindo outras funções do VEGF e seus receptores na cascata do desenvolvimento pulmonar 20 . O mecanismo pelo qual a corticoterapia age sobre a produção do VEGF e de seus receptores não está completamente elucidado.…”

“…Esta relação foi confirmada no presente estudo, onde as alterações do VEGFR-2 e dos pneumócitos II ocorriam concomitantemente. O VEGF induz rapidamente a conversão do glicogênio do pneumócito II em surfactante e essa ação parece ser mediada principalmente pelo FlK-1 que também sofre ação do glicocorticóide 6,20 . O VEGFR-2(Flk-1) é expresso nas fases inicias do desenvolvimento pulmonar, enquanto o VEGFR-1(Flt-1) aumenta nas fases tardias desse desenvolvimento.…”

Effects of Oxidative Stress and Antenatal Corticosteroids on the Pulmonary Expression of Vascular Endothelial Growth Factor (VEGF) and Alveolarization

“…In a murine model, Bhatt et al (Bhatt et al, 2000) observed that VEGF mRNA levels increased three-fold during the first two weeks of postnatal age: i.e., the alveolarization phase and expansion of the microvasculature; VEGFR-2 mRNA increased in parallel. In those studies, performed by in situ hybridization, the authors demonstrated that VEGF mRNA was mainly located in the epithelial cells of the distal air spaces.…”

“…Conversely, a study in mice conducted by Bhatt et al (Bhatt et al, 2000), who administered dexamethasone (0.1-5 mg/ Kg/ day) from postnatal day 6 to 9, analyzed VEGF mRNA and VEGFR-2 mRNA levels in lungs, and found that VEGF and VEGFR-2 increased with increasing doses of dexamethasone. They also analyzed the effects of dexamethasone on the amount of mRNA HLF, which has been associated with an increased transcription of VEGF in normoxia and hypoxia.…”

“…Vascular endothelial growth factor (VEGF) is a potent mitogen for endothelial cells (Ferrara et al, 1997;Lassus et al, 1999) as well as being chemotactic for these cells, and it is one of the most potent mediators of vascular regulation (Bhatt et al, 2000). Regarding water and proteins, VEGF exerts a potent effect on vascular permeability (Dvorak et al, 1995).…”