Heterozygous deficiency of delta-catenin impairs pathological angiogenesis.
Vascular and neuronal networks share a similar branching morphology, and emerging evidence implicates common mechanisms in the formation of both systems. delta-Catenin is considered a neuronal catenin regulating neuron cell-cell adhesion and cell motility. Here, we report expression of delta-catenin in vascular endothelium, and show that deletion of only one allele of delta-catenin is sufficient to impair endothelial cell motility and vascular assembly in vitro and pathological angiogenesis in vivo, thereby inhibiting tumor growth and wound healing. In contrast, deletion of one or both allele of delta-catenin had no effects on hormone-induced physiological angiogenesis in the uterus. Molecular analysis confirmed a gene dosage effect of delta-catenin on Rho GTPase activity. Moreover, we show that inflammatory cytokines, but not angiogenic factors, regulate delta-catenin expression, and the levels of delta-catenin positively correlate to human lung cancers. Collectively, our data suggest that inflammation, commonly associated with disease conditions, induces delta-catenin expression that specifically regulates pathological, and not physiological, angiogenesis. Because only pathological angiogenesis is sensitive to decreased levels of delta-catenin, this may provide a good target for antiangiogenic therapy.
DeBusk
Laura M
LM
Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Boelte
Kimberly
K
Min
Yongfen
Y
Lin
P Charles
PC
D000483:Alleles; D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051177:Catenins / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006579:Heterozygote; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020298:U937 Cells; D014599:Uterus / Q000378:metabolism / Q000473:pathology; D014945:Wound Healing / Q000235:genetics; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism; D000095002:Delta Catenin
D051177:Catenins; D016207:Cytokines; D018836:Inflammation Mediators; D054460:rho-Associated Kinases; D000095002:Delta Catenin