Previous studies have linked elastin remodeling with the development of new blood vessels from existing ones (angiogenesis).1-2 In the lung, elastin remodeling was associated with proliferating (angiogenin positive) cells.3 To test whether Cela1 regulated angiogenesis, we first silenced Cela1 in an embryonic mouse lung mesenchymal/endothelial cell line (MFLM4). Cela1 silencing inhibited tubulogenesis (Figure 4A-B). In vitro gain of function experiments demonstrated that overexpression of Cela1 could trigger tubulogenesis in lung fibroblasts (Figure 4C-D). Using vascular-labeled Danio, silencing of a Cela1 orthologue impaired angiogenesis of the segmental vasculature and co-injecting murine Cela1 mRNA rescued this phenotype (Figure 4E-G). Anti-Cela1 antibody inhibited microvascular invasion in a subcutaneous matrigel plug assay (Figure 4H-I). Demonstrating therapeutic potential, Cela1 expression was associated with the increased microvascular density in a mouse model of lung adenocarcinoma (Figure 4J-K). All of these data support an important role for Cela1 in regulating lung microvascular morphogenesis.
Our current studies are investigating the mechanisms by which Cela1 exerts its angiogenic effects and whether these mechanisms can be targeted to improve pulmonary health.
1Pocza P, et al. Locally generative VGVAGP and VAPG elastin-derived peptides amplify melanoma invasion via the galectin-3 receptor. Int J Cancer. (122)9:1972-80. May 2008.
2Robinet A, et al. Elastin-derived peptides enhance angiogenesis by promoting endothelial cell migration and tubulogenesis through upregulation of MT1-MMP. J Cell Sci. (118)2:L343-56. Jan 2005.
3Liu S, Young SM, Varisco BM. Dynamic expression of chymotrypsin-like elastase 1 over the course of murine lung development. Am J Physiol Lung Cell Mol Physiol. (306)12:L1104-16. Jun 2014.