title: Organ-specific lymphangiectasia, arrested lymphatic sprouting, and maturation defects resulting from gene-targeting of the PI3K regulatory isoforms p85alpha, p55alpha, and p50alpha.
abstract: The phosphoinositide 3-kinase (PI3K) family has multiple vascular functions, but the specific regulatory isoform supporting lymphangiogenesis remains unidentified. Here, we report that deletion of the Pik3r1 gene, encoding the regulatory subunits p85alpha, p55alpha, and p50alpha impairs lymphatic sprouting and maturation, and causes abnormal lymphatic morphology, without major impact on blood vessels. Pik3r1 deletion had the most severe consequences among gut and diaphragm lymphatics, which share the retroperitoneal anlage, initially suggesting that the Pik3r1 role in this vasculature is anlage-dependent. However, whereas lymphatic sprouting toward the diaphragm was arrested, lymphatics invaded the gut, where remodeling and valve formation were impaired. Thus, cell-origin fails to explain the phenotype. Only the gut showed lymphangiectasia, lymphatic up-regulation of the transforming growth factor-beta co-receptor endoglin, and reduced levels of mature vascular endothelial growth factor-C protein. Our data suggest that Pik3r1 isoforms are required for distinct steps of embryonic lymphangiogenesis in different organ microenvironments, whereas they are largely dispensable for hemangiogenesis.
authors.affiliation: Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, Maine, USA.
authors.forename: Carla
authors.initials: C
authors.lastname: Mouta-Bellum
authors.forename: Aleksander
authors.initials: A
authors.lastname: Kirov
authors.forename: Laura
authors.initials: L
authors.lastname: Miceli-Libby
authors.forename: Maria L
authors.initials: ML
authors.lastname: Mancini
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Petrova
authors.forename: Lucy
authors.initials: L
authors.lastname: Liaw
authors.forename: Igor
authors.initials: I
authors.lastname: Prudovsky
authors.forename: Philip E
authors.initials: PE
authors.lastname: Thorpe
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Miura
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.forename: David A
authors.initials: DA
authors.lastname: Fruman
authors.forename: Calvin P H
authors.initials: CP
authors.lastname: Vary
mesh_terms: D000818:Animals; D000831:Animals, Newborn / Q000033:anatomy & histology / Q000502:physiology; D018390:Gene Targeting; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008200:Lymphangiectasis / Q000473:pathology / Q000503:physiopathology; D042583:Lymphangiogenesis / Q000502:physiology*; D042601:Lymphatic Vessels / Q000002:abnormalities / Q000033:anatomy & histology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D007527:Isoenzymes; D021122:Protein Subunits; D019869:Phosphatidylinositol 3-Kinases
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