Organ-specific lymphangiectasia, arrested lymphatic sprouting, and maturation defects resulting from gene-targeting of the PI3K regulatory isoforms p85α, p55α, and p50α

Carla Mouta-Bellum, Aleksander Kirov, Laura Miceli-Libby, Maria L. Mancini, Tatiana V. Petrova, Lucy Liaw, Igor Prudovsky, Philip E. Thorpe, Naoyuki Miura, Lewis C. Cantley, Kari Alitalo, David A. Fruman, Calvin P H Vary

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

The phosphoinositide 3-kinase (PI3K) family has multiple vascular functions, but the specific regulatory soform supporting lymphangiogenesis remains unidentified. Here, we report that deletion of the Pik3r1 gene, encoding the regulatory subunits p85α, p55α, and p50α 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-β 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.

Original languageEnglish (US)
Pages (from-to)2670-2679
Number of pages10
JournalDevelopmental Dynamics
Volume238
Issue number10
DOIs
StatePublished - Oct 1 2009

Keywords

  • Lymphangiogenesis
  • Phosphatidyl inositol 3-kinase

ASJC Scopus subject areas

  • Developmental Biology

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    Mouta-Bellum, C., Kirov, A., Miceli-Libby, L., Mancini, M. L., Petrova, T. V., Liaw, L., Prudovsky, I., Thorpe, P. E., Miura, N., Cantley, L. C., Alitalo, K., Fruman, D. A., & Vary, C. P. H. (2009). Organ-specific lymphangiectasia, arrested lymphatic sprouting, and maturation defects resulting from gene-targeting of the PI3K regulatory isoforms p85α, p55α, and p50α. Developmental Dynamics, 238(10), 2670-2679. https://doi.org/10.1002/dvdy.22078