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This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: 296/1/L71    most recent 90452.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Schwarz, M. A. Articles by Zheng, H. Search for Related Content PubMed PubMed Citation Articles by Schwarz, M. A. Articles by Zheng, H.

Emerging pulmonary vasculature lacks fate specification

¹University of Texas Southwestern Medical Center at Dallas, Dallas, Texas; ²Drexel University College of Medicine, Philadelphia, Pennsylvania; ³Nova Southeastern University, Fort Lauderdale-Davie, Florida; and ⁴University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey

Submitted 20 August 2008 ; accepted in final form 23 October 2008

Lung morphogenesis requires precise coordination between branching morphogenesis and vascularization to generate distal airways capable of supporting respiration at the cell-cell interface. The specific origins and types of blood vessels that initially form in the lung, however, remain obscure. Herein, we definitively show that during the early phases of lung development [i.e., embryonic day (E) 11.5], functional vessels, replete with blood flow, are restricted to the mesenchyme, distal to the epithelium. However, by day E14.5, and in response to epithelial-derived VEGF signals, functional vessels extend from the mesenchyme to the epithelial interface. Moreover, these vessels reside adjacent to multipotent mesenchymal stromal cells that likely play a regulatory role in this process. As well as and distinct from the systemic vasculature, immunostaining for EphrinB2 and EphB4 revealed that arterial and venous identity is not distinguishable in emergent pulmonary vasculature. Collectively, this study provides evidence that lung vascularization initially originates in the mesenchyme, distal to the epithelium, and that arterial-venous specification does not exist in the early lung. At a mechanistic level, we show that basilar epithelial VEGF prompts endothelial cells to move toward the epithelium where they undergo morphogenesis during the proliferative, canalicular stage. Thus our findings challenge existing notions of vascular origin and identity during development.

vascular; vessel; EphrinB2; EphB4; platelet endothelial cell adhesion molecule-1; lectin; blood flow; fate specification