PMID:17607303

Citation	Sullivan, KM, Bissonnette, R, Yanagisawa, H, Hussain, SN and Davis, EC (2007) Fibulin-5 functions as an endogenous angiogenesis inhibitor. Lab. Invest. 87:818-27
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.
Links	PubMed Online version:10.1038/labinvest.3700594
Keywords	Adaptor Proteins, Vesicular Transport/metabolism; Angiogenesis Inhibitors/physiology; Angiopoietins/biosynthesis; Animals; Cell Movement; Endothelial Cells/metabolism; Endothelium, Vascular/metabolism; Extracellular Matrix Proteins/genetics; Extracellular Matrix Proteins/physiology; Fibroblasts/physiology; Mice; Mice, Knockout; Muscle, Smooth, Vascular/metabolism; Neovascularization, Physiologic; Polyvinyl Alcohol; Recombinant Proteins/genetics; Skin/blood supply; Surgical Sponges; Thoracic Arteries/physiology; Vascular Endothelial Growth Factor A/biosynthesis
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:FBLN5		GO:0016525: negative regulation of angiogenesis	ECO:0000315:		P		Figure 1 shows “in fbln5-/- mice, the vessel appeared to have an increased number of small, tortuous branches compared with fbln5+/- and wild-type mice. The overall length of the vessel measured between the start and end points, however, was unchanged (Figure 1e), suggesting that the increased number of vessels branching from the long thoracic artery of fbln5-/- mice was not a consequence of a longer vessel.”	complete CACAO 11071
MOUSE:FBLN5		GO:0000122: negative regulation of transcription from RNA polymerase II promoter	ECO:0000315:		P		Figure 4e and Figure 5a	complete CACAO 11072
MOUSE:FBLN5		GO:0045944: positive regulation of transcription from RNA polymerase II promoter	ECO:0000315:		P		Figure 5b: "ESE-1, was slightly downregulated in fbln5 -/- SMCs" Looking at the figure, mRNA expression is what is measured.	complete CACAO 11133

References

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