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Spatiotemporal Expression of flk-1 in Pulmonary Epithelial Cells during Lung Development

¹ University of Giessen Lung Center, Department of Internal Medicine, University Hospital Giessen, Giessen, Germany; ² Department of Pathology, University of Regensburg, Regensburg, Germany; ³ Department of Anatomy and Histology, Flinders University Adelaide, Adelaide, South Australia; ⁴ Department of Pathology, University of Dresden, Dresden, Germany

Correspondence and requests for reprints should be addressed to Katrin Ahlbrecht, M.D., Medical Clinic 2, University Clinic Giessen, Klinikstrasse 36, 35392 Giessen, Germany. E-mail: Katrin.Ahlbrecht{at}innere.med.uni-giessen.de

Vascular endothelial growth factor-A (VEGF-A) responsive effects mediated via the receptors fetal liver kinase-1 (flk-1) and fms-like tyrosine kinase (flt-1), are key processes of pulmonary vascular development. Flk-1 has been shown to be involved in early embryonic lung epithelial to endothelial crosstalk and branching morphogenesis. Recent reports suggested a role of VEGF-A in lung epithelial cell function. Based on these observations, we hypothesize that epithelial flk-1 has a unique function in pulmonary development. Thus, the aim of this study is to elucidate spatiotemporal expression of flk-1 during lung development with respect to the epithelial system. Embryonic lungs were screened for flk-1 messenger RNA and protein at daily intervals, including postnatal stages. From Embryonic Day (ED) 12.5 through ED 15.5, flk-1 expression was restricted to the early vascular primitive network, while from ED 16.5 on flk-1 was detectable in the epithelial system and persisted there postnatally. At postnatal stages, flk-1 expression was increasingly restricted to individual cells in the alveolar septa. Isolation and in vitro cultivation of alveolar epithelial cells confirmed flk-1 expression and showed VEGF secretion into the supernatant. To our knowledge, this is the first murine study characterizing epithelial flk-1 expression at different stages throughout lung organogenesis until birth and at postnatal stages. To confirm epithelial flk-1 expression, we performed reporter gene analysis of the flk-1 promoter in vivo. Investigations on transgenic mouse strains, containing either a complete or incomplete flk-1 promoter driving expression of the lacZ reporter gene, suggested differential flk-1 regulation in endothelial and epithelial cells.

Key Words: VEGF • VEGF receptor-2 • alveolarization • alveolar epithelial cells • lung development

CLINICAL RELEVANCE This work shows new expression patterns of flk-1 during lung development and postnatally with special respect to the pulmonary epithelial system. These data can be the basis for further studies elucidating a role of epithelial flk-1 function.