TY - JOUR
T1 - A perfusion-independent role of blood vessels in determining branching stereotypy of lung airways
AU - Lazarus, Alon
AU - Del-Moral, Pierre Marie
AU - Ilovich, Ohad
AU - Mishani, Eyal
AU - Warburton, David
AU - Keshet, Eli
PY - 2011/6/1
Y1 - 2011/6/1
N2 - 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.
AB - 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.
KW - Branching morphogenesis
KW - Lung development
KW - Mouse
KW - Vascular network
UR - http://www.scopus.com/inward/record.url?scp=79956320721&partnerID=8YFLogxK
U2 - 10.1242/dev.060723
DO - 10.1242/dev.060723
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C2 - 21558382
AN - SCOPUS:79956320721
SN - 0950-1991
VL - 138
SP - 2359
EP - 2368
JO - Journal of Embryology and Experimental Morphology
JF - Journal of Embryology and Experimental Morphology
IS - 11
ER -