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 language | English (US) |
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Pages (from-to) | 818-827 |
Number of pages | 10 |
Journal | Laboratory Investigation |
Volume | 87 |
Issue number | 8 |
DOIs | |
State | Published - 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