Defective endothelial cell migration in the absence of Cdc42 leads to capillary-venous malformations

TY - JOUR

T1 - Defective endothelial cell migration in the absence of Cdc42 leads to capillary-venous malformations

AU - Laviña, Bàrbara

AU - Castro, Marco

AU - Niaudet, Colin

AU - Cruys, Bert

AU - Álvarez-Aznar, Alberto

AU - Carmeliet, Peter

AU - Bentley, Katie

AU - Brakebusch, Cord

AU - Betsholtz, Christer

AU - Gaengel, Konstantin

N1 - © 2018. Published by The Company of Biologists Ltd.

PY - 2018/7/2

Y1 - 2018/7/2

N2 - Formation and homeostasis of the vascular system requires several coordinated cellular functions, but their precise interplay during development and their relative importance for vascular pathologies remain poorly understood. Here, we investigated the endothelial functions regulated by Cdc42 and their in vivo relevance during angiogenic sprouting and vascular morphogenesis in the postnatal mouse retina. We found that Cdc42 is required for endothelial tip cell selection, directed cell migration and filopodia formation, but dispensable for cell proliferation or apoptosis. Although the loss of Cdc42 seems generally compatible with apical-basal polarization and lumen formation in retinal blood vessels, it leads to defective endothelial axial polarization and to the formation of severe vascular malformations in capillaries and veins. Tracking of Cdc42-depleted endothelial cells in mosaic retinas suggests that these capillary-venous malformations arise as a consequence of defective cell migration, when endothelial cells that proliferate at normal rates are unable to re-distribute within the vascular network.

AB - Formation and homeostasis of the vascular system requires several coordinated cellular functions, but their precise interplay during development and their relative importance for vascular pathologies remain poorly understood. Here, we investigated the endothelial functions regulated by Cdc42 and their in vivo relevance during angiogenic sprouting and vascular morphogenesis in the postnatal mouse retina. We found that Cdc42 is required for endothelial tip cell selection, directed cell migration and filopodia formation, but dispensable for cell proliferation or apoptosis. Although the loss of Cdc42 seems generally compatible with apical-basal polarization and lumen formation in retinal blood vessels, it leads to defective endothelial axial polarization and to the formation of severe vascular malformations in capillaries and veins. Tracking of Cdc42-depleted endothelial cells in mosaic retinas suggests that these capillary-venous malformations arise as a consequence of defective cell migration, when endothelial cells that proliferate at normal rates are unable to re-distribute within the vascular network.

U2 - 10.1242/dev.161182

DO - 10.1242/dev.161182

M3 - Journal article

C2 - 29853619

SN - 0950-1991

VL - 145

JO - Development (Cambridge, England)

JF - Development (Cambridge, England)

IS - 13

M1 - dev161182

ER -