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Blockade of VEGF-C signaling inhibits lymphatic malformations driven by oncogenic PIK3CA mutation.
- Source :
- Nature Communications; 6/8/2020, Vol. 11 Issue 1, p1-14, 14p
- Publication Year :
- 2020
-
Abstract
- Lymphatic malformations (LMs) are debilitating vascular anomalies presenting with large cysts (macrocystic) or lesions that infiltrate tissues (microcystic). Cellular mechanisms underlying LM pathology are poorly understood. Here we show that the somatic PIK3CA<superscript>H1047R</superscript> mutation, resulting in constitutive activation of the p110α PI3K, underlies both macrocystic and microcystic LMs in human. Using a mouse model of PIK3CA<superscript>H1047R</superscript>-driven LM, we demonstrate that both types of malformations arise due to lymphatic endothelial cell (LEC)-autonomous defects, with the developmental timing of p110α activation determining the LM subtype. In the postnatal vasculature, PIK3CA<superscript>H1047R</superscript> promotes LEC migration and lymphatic hypersprouting, leading to microcystic LMs that grow progressively in a vascular endothelial growth factor C (VEGF-C)-dependent manner. Combined inhibition of VEGF-C and the PI3K downstream target mTOR using Rapamycin, but neither treatment alone, promotes regression of lesions. The best therapeutic outcome for LM is thus achieved by co-inhibition of the upstream VEGF-C/VEGFR3 and the downstream PI3K/mTOR pathways. Lymphatic malformation (LM) is a debilitating often incurable vascular disease. Using a mouse model of LM driven by a disease-causative PIK3CA mutation, the authors show that vascular growth is dependent on the upstream lymphangiogenic VEGF-C signalling, permitting effective therapeutic intervention. [ABSTRACT FROM AUTHOR]
- Subjects :
- VASCULAR endothelial growth factors
HUMAN abnormalities
ARNOLD-Chiari deformity
Subjects
Details
- Language :
- English
- ISSN :
- 20411723
- Volume :
- 11
- Issue :
- 1
- Database :
- Complementary Index
- Journal :
- Nature Communications
- Publication Type :
- Academic Journal
- Accession number :
- 143660369
- Full Text :
- https://doi.org/10.1038/s41467-020-16496-y