Divergent roles of prokineticin receptors in the endothelial cells: Angiogenesis and fenestration

Célia Guilini, Kyoji Urayama, Gulen Turkeri, Deniz B. Dedeoglu, Hitoshi Kurose, Nadia Messaddeq, Canan G. Nebigil

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

Prokineticins are secreted peptides that activate two G protein-coupled receptors: PKR1 and PKR2. Prokineticins induce angiogenesis and fenestration, but the cognate receptors involved in these functions are unknown. We hypothesized a role for prokineticin receptor signaling pathways and expression profiles in determining the selective effects of prokineticins on coronary endothelial cells (H5V). Activation of the PKR1/ MAPK/Akt signaling pathway stimulates proliferation, migration, and angiogenesis in H5V cells, in which PKR1 predominates over PKR2. PKR1 was colocalized with Gα11 and was internalized following the stimulation of these cells with prokineticin-2. Knock down of PKR1 or Gα11 expression in H5V cells effectively inhibited prokineticin-2-induced vessel formation and MAPK/Akt activation, indicating a role for PKR1/Gα11 in this process. However, in conditions in which PKR2 predominated over PKR1, these cells displayed a fenestrated endothelial cell phenotype. H5V cells overexpressing PKR2 displayed large numbers of multivesicular bodies and caveolar clusters and a disruption of the distribution of zonula occluden-1 tight junction protein. Prokineticin-2 induced the colocalization of PKR2 with Gα12, and activated Gα12, which bound to zonula occluden-1 to trigger the degradation of this protein in these cells. Prokineticin-2 induced the formation of vessel-like structures by human aortic endothelial cells expressing only PKR1, and disorganized the tight junctions in human hepatic sinusoidal endothelial cells expressing only PKR2, confirming the divergent roles of these receptors. Our findings show the functional characteristics of coronary endothelial cells depend on the expression of PKR1 and PKR2 levels and the divergent signaling pathways used by these receptors.

Original languageEnglish
Pages (from-to)H844-H852
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume298
Issue number3
DOIs
Publication statusPublished - Mar 1 2010

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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