Fibulin-5 functions as an endogenous angiogenesis inhibitor

Kaitlyn M. Sullivan, Rachel Bissonnette, Hiromi Yanagisawa, Sabah N. Hussain, Elaine C. Davis

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

Ablation of the fibulin-5 gene (fbln5) in mice results in loose skin, emphysematous lungs and tortuous vessels. Additionally, fbln5-/- animals display an apparent increase in vascular sprouting from systemic and cutaneous vessels. From these observations, we hypothesized that a de-regulation of vascular sprouting occurs in the absence of endogenous fibulin-5. To test this hypothesis, vascular sprouts from the long thoracic artery were quantified and polyvinyl alcohol sponges were implanted subcutaneously in wild-type and fbln5-/- mice to assess fibrovascular invasion. Results showed a significant increase in in situ sprouting from vessels in fbln5-/- mice and a significant increase in vascular invasion, with no increase in fibroblast migration, into sponges removed from fbln5-/- mice compared with wild-type mice. Localization of fibulin-5 in wild-type mice showed the protein to be present subjacent to endothelial cells (ECs) in established vessels at the periphery of the sponge, and as a component of the newly formed, loose connective tissue within the sponge. These results suggest that fibulin-5 could function as an inhibitor molecule in initial sprouting and/or migration of ECs. To elucidate the molecular mechanism that drives the increased angiogenesis in the absence of fibulin-5, expression of vascular endothelial growth factor (VEGF) and the angiopoietins (Angs) was determined in sponges implanted for 12 days in wild-type and fbln5-/- mice. Quantitative RT-PCR showed message levels for VEGF and all three Angs to be elevated by several fold in the area of invasion of sponges from fbln5-/- mice compared with wild-type mice. Expression of Ang-1 was also shown to be elevated (30-fold) in vitro in aortic smooth muscle cells isolated from fbln5 -/- mice when compared with wild-type cells, with no change in the expression of the Ang-1 mediating transcription factor, ESE-1. Taken together, these results suggest that the normal angiogenic process is enhanced in the absence of fibulin-5.

Original languageEnglish (US)
Pages (from-to)818-827
Number of pages10
JournalLaboratory Investigation
Volume87
Issue number8
DOIs
StatePublished - Aug 11 2007

Keywords

  • Angiogenesis
  • Angiopoietins
  • Fibulin-5
  • Knockout mouse
  • VEGF
  • Vascular sprouting

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

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  • Cite this

    Sullivan, K. M., Bissonnette, R., Yanagisawa, H., Hussain, S. N., & Davis, E. C. (2007). Fibulin-5 functions as an endogenous angiogenesis inhibitor. Laboratory Investigation, 87(8), 818-827. https://doi.org/10.1038/labinvest.3700594