Endoglin haploinsufficiency promotes fibroblast accumulation during wound healing through Akt activation

PLoS One. 2013;8(1):e54687. doi: 10.1371/journal.pone.0054687. Epub 2013 Jan 17.

Abstract

Accurate regulation of dermal fibroblast function plays a crucial role in wound healing. Many fibrotic diseases are characterized by a failure to conclude normal tissue repair and the persistence of fibroblasts inside lesions. In the present study we demonstrate that endoglin haploinsufficiency promotes fibroblast accumulation during wound healing. Moreover, scars from endoglin-heterozygous (Eng(+/-)) mice show persisting fibroblasts 12 days after wounding, which could lead to a fibrotic scar. Endoglin haploinsufficiency results in increased proliferation and migration of primary cultured murine dermal fibroblasts (MDFs). Moreover, Eng(+/-) MDF have diminished responses to apoptotic signals compared with control cells. Altogether, these modifications could explain the augmented presence of fibroblasts in Eng(+/-) mice wounds. We demonstrate that endoglin expression regulates Akt phosphorylation and that PI3K inhibition abolishes the differences in proliferation between endoglin haploinsufficient and control cells. Finally, persistent fibroblasts in Eng(+/-) mice wound co-localize with a greater degree of Akt phosphorylation. Thus, endoglin haploinsufficiency seems to promote fibroblast accumulation during wound healing through the activation of the PI3K/Akt pathway. These studies open new non-Smad signaling pathway for endoglin regulating fibroblast cell function during wound healing, as new therapeutic opportunities for the treatment of fibrotic wounds.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cicatrix / metabolism
  • Cicatrix / pathology
  • Endoglin
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Fibroblasts / physiology
  • Haploinsufficiency
  • Heterozygote
  • Intracellular Signaling Peptides and Proteins* / genetics
  • Intracellular Signaling Peptides and Proteins* / metabolism
  • Mice
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction
  • Skin / injuries
  • Skin / metabolism
  • Skin / pathology
  • Transcriptional Activation
  • Wound Healing / physiology*

Substances

  • Endoglin
  • Eng protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt

Grants and funding

This work was supported by grants from the Junta de Castilla y León (SA052A06 and SA029A09) to ARB and SA001/C05 to JMLN, and Ministerio de Ciencia e Innovación (BFU2004-00285/BFI, and SAF2007-63893 to JMLN) and the Instituto de Salud Carlos III, (RETIC RedInRen RD/0016). MP was a holder of a fellowship from the Junta de Castilla y Leon, and SV was a fellowship holder of the Spanish Ministerio de Educación y Ciencia. The Renal and Cardiovascular Physiology Unit is an Excellence Research Group awarded by Junta de Castilla y Leon. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.