Blocking angiogenesis with peptides that inhibit the activity of procollagen C-endopeptidase

Abstract

Procollagen C-endopeptidase (BMP-1) is one of two key enzymes crucial for conversion of fibrillar procollagens to self-assembling collagen monomers. Recently, we have reported inhibition of the largest variant of BMP-1, a recombinant mammalian tolloid (mTld) in vitro, on procollagen type I using peptides with amino acid sequences in chordin conserved across different species. Here, we tested the same peptides as potent blockers of angiogenesis ex vivo in cultured rings of rat aorta, in vivo in chick embryos, and in vitro in cell cultures. Our results revealed that the peptides inhibited the angiogenic activity in rat aorta explants at micromolar concentrations; they also blocked blood vessel growth in chick embryos. The peptides were also tested on three types of human cells, e.g., umbilical vein endothelium, skin fibroblasts, and tumor HT-1080 cells. Since the three types of cells proliferated at a significantly lower rate or did not proliferate at all, we conclude that the anti-angiogenic effect observed in rat aorta ring explants and in chick embryos was related to inhibition of cell proliferation. In conclusion, we showed the ability to inhibit angiogenesis by blocking the activity of procollagen C-endopeptidase. The results strongly indicate crucial role(s) of this metalloproteinase in the formation of new blood vessels and maintenance of their growth.

Metalloproteinases in Drosophila to Humans That Are Central Players in Developmental Processes

“…B/TP cleavage of perlecan liberates the anti-angiogenic fragment endorepellin (67). However, peptides that inhibit mTLD in vitro may reduce angiogenesis in some systems (69). Thus, B/TPs may balance regulation of angiogenesis by assisting in blood vessel growth while releasing anti-angiogenic factors to prevent excessive angiogenesis.…”

Functional and structural studies of tolloid-like 1 mutants associated with atrial-septal defect 6

“…However, blocking their activities inhibited the growth of blood vessels in chick embryos. In vitro studies have shown that this is due to the reduction in the rate of endothelial cell proliferation [62].…”

Role of Extracellular Matrix and Inflammation in Abdominal Aortic Aneurysm

“…Their action is critical for the production of collagen fibrils in connective tissue. In aortal walls, the lack of their activity leads to weaker wall structure, possible development of aneurysm and its rupture, among other general tissue problems [ 23 , 24 , 25 ]. Genetic, inherited diseases manifested by the development of aneurysms are some cases of progressively deforming type 3 osteogenesis imperfecta (OI) with a mutation in the gene encoding BMP1, [ 26 ] also classified as OI type XIII [ 27 ], dermatosparaxis with mutations in ADAMTS-2 [ 28 ], and mutations in COL3A1, causing the vascular type of Ehlers–Danlos Syndrome [ 29 ].…”

“…They are classified to six different families, depending on the specific substrate of the ECM component [ 34 , 35 ]. On the basis of the substrates and the organization of the domains of metalloproteinases, the following families of these enzymes have been proposed: collagenases, gelatinases, stromelysins, matrilysins, metalloelastase, and membrane-type (MT) MMPs ( Table 2 ) [ 4 , 23 , 24 ].…”