LKB1 in endothelial cells is required for angiogenesis and TGFbeta-mediated vascular smooth muscle cell recruitment.
Inactivation of the tumor suppressor kinase Lkb1 in mice leads to vascular defects and midgestational lethality at embryonic day 9-11 (E9-E11). Here, we have used conditional targeting to investigate the defects underlying the Lkb1(-/-) phenotype. Endothelium-restricted deletion of Lkb1 led to embryonic death at E12.5 with a loss of vascular smooth muscle cells (vSMCs) and vascular disruption. Transforming growth factor beta (TGFbeta) pathway activity was reduced in Lkb1-deficient endothelial cells (ECs), and TGFbeta signaling from Lkb1(-/-) ECs to adjacent mesenchyme was defective, noted as reduced SMAD2 phosphorylation. The addition of TGFbeta to mutant yolk sac explants rescued the loss of vSMCs, as evidenced by smooth muscle alpha actin (SMA) expression. These results reveal an essential function for endothelial Lkb1 in TGFbeta-mediated vSMC recruitment during angiogenesis.
Genome-Scale Biology Program and Institute of Biomedicine, Biomedicum Helsinki, 00014 University of Helsinki, Finland.
Anou
A
Londesborough
Kari
K
Vaahtomeri
Marianne
M
Tiainen
Pekka
P
Katajisto
Niklas
N
Ekman
Tea
T
Vallenius
Tomi P
TP
Mäkelä
D055372:AMP-Activated Protein Kinases; D000818:Animals; D004622:Embryo, Mammalian / Q000098:blood supply / Q000196:embryology / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D004727:Endothelium / Q000196:embryology / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D018507:Gene Expression Regulation, Developmental; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000098:blood supply* / Q000196:embryology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D046509:Tissue Culture Techniques; D053773:Transforming Growth Factor beta1 / Q000378:metabolism* / Q000494:pharmacology
D053773:Transforming Growth Factor beta1; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases