title: A perfusion-independent role of blood vessels in determining branching stereotypy of lung airways.
abstract: Blood vessels have been shown to play perfusion-independent roles in organogenesis. Here, we examined whether blood vessels determine branching stereotypy of the mouse lung airways in which coordinated branching of epithelial and vascular tubes culminates in their co-alignment. Using different ablative strategies to eliminate the lung vasculature, both in vivo and in lung explants, we show that proximity to the vasculature is indeed essential for patterning airway branching. Remarkably, although epithelial branching per se proceeded at a nearly normal rate, branching stereotypy was dramatically perturbed following vascular ablation. Specifically, branching events requiring a rotation to change the branching plane were selectively affected. This was evidenced by either the complete absence or the shallow angle of their projections, with both events contributing to an overall flat lung morphology. Vascular ablation also led to a high frequency of ectopic branching. Regain of vascularization fully rescued arrested airway branching and restored normal lung size and its three-dimensional architecture. This role of the vasculature is independent of perfusion, flow or blood-borne substances. Inhibition of normal branching resulting from vascular loss could be explained in part by perturbing the unique spatial expression pattern of the key branching mediator FGF10 and by misregulated expression of the branching regulators Shh and sprouty2. Together, these findings uncovered a novel role of the vasculature in organogenesis, namely, determining stereotypy of epithelial branching morphogenesis.
authors.affiliation: Department of Molecular Biology, Hebrew University-Hadassah Medical School, and Department of Medical Biophysics and Nuclear Medicine, Hadassah Hebrew University Hospital, Jerusalem 91120, Israel.
authors.forename: Alon
authors.initials: A
authors.lastname: Lazarus
authors.forename: Pierre Marie
authors.initials: PM
authors.lastname: Del-Moral
authors.forename: Ohad
authors.initials: O
authors.lastname: Ilovich
authors.forename: Eyal
authors.initials: E
authors.lastname: Mishani
authors.forename: David
authors.initials: D
authors.lastname: Warburton
authors.forename: Eli
authors.initials: E
authors.lastname: Keshet
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002450:Cell Communication; D042783:Endothelial Cells / Q000502:physiology; D051526:Fibroblast Growth Factor 10 / Q000096:biosynthesis; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000096:biosynthesis; D017403:In Situ Hybridization; D047908:Intracellular Signaling Peptides and Proteins; D008168:Lung / Q000098:blood supply* / Q000196:embryology*; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D009024:Morphogenesis; D018919:Neovascularization, Physiologic; D009924:Organ Culture Techniques; D038081:Organogenesis; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C496464:Fgf10 protein, mouse; D051526:Fibroblast Growth Factor 10; D053823:Hedgehog Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C465570:Shh protein, mouse; D042461:Vascular Endothelial Growth Factor A; D017346:Protein Serine-Threonine Kinases; C118389:Spry2 protein, mouse