Lysyl oxidase interactions with transforming growth factor- β during angiogenesis are mediated by endothelin 1

Crosstalk between multiple components underlies the formation of mature vessels. Although the players involved in angiogenesis have been identified, mechanisms underlying the crosstalk between them are still unclear. Using the ex vivo aortic ring assay, we set out to dissect the interactions between two key angiogenic signaling pathways, vascular endothelial growth factor (VEGF) and transforming growth factor β (TGFβ), with members of the lysyl oxidase (LOX) family of matrix modifying enzymes. We find an interplay between VEGF, TGFβ, and the LOXs is essential for the formation of mature vascular smooth muscle cells (vSMC)- coated vessels. RNA sequencing analysis further identified an interaction with the endothelin- 1 pathway. Our work implicates endothelin- 1 downstream of TGFβ in vascular maturation and demonstrate the complexity of processes involved in generating vSMC- coated vessels.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/169278/1/fsb221824.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/169278/2/fsb221824-sup-0006-TableS1.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/169278/3/fsb221824-sup-0007-TableS2.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/169278/4/fsb221824_am.pd

Initiation of fibronectin fibrillogenesis is an enzyme-dependent process

Summary: Fibronectin fibrillogenesis and mechanosensing both depend on integrin-mediated force transmission to the extracellular matrix. However, force transmission is in itself dependent on fibrillogenesis, and fibronectin fibrils are found in soft embryos where high forces cannot be applied, suggesting that force cannot be the sole initiator of fibrillogenesis. Here, we identify a nucleation step prior to force transmission, driven by fibronectin oxidation mediated by lysyl oxidase enzyme family members. This oxidation induces fibronectin clustering, which promotes early adhesion, alters cellular response to soft matrices, and enhances force transmission to the matrix. In contrast, absence of fibronectin oxidation abrogates fibrillogenesis, perturbs cell-matrix adhesion, and compromises mechanosensation. Moreover, fibronectin oxidation promotes cancer cell colony formation in soft agar as well as collective and single-cell migration. These results reveal a force-independent enzyme-dependent mechanism that initiates fibronectin fibrillogenesis, establishing a critical step in cell adhesion and mechanosensing

Blocking surgically induced lysyl oxidase activity reduces the risk of lung metastases

Abstract Surgery remains the most successful curative treatment for cancer. However, some patients with early-stage disease who undergo surgery eventually succumb to distantmetastasis. Here, we show that in response to surgery, the lungs become more vulnerable to metastasis due to extracellular matrix remodeling. Mice that undergo surgery or that are preconditioned with plasma from donor mice that underwent surgery succumb to lung metastases earlier than controls. Increased lysyl oxidase (LOX) activity and expression, fibrillary collagen crosslinking, and focal adhesion signaling contribute to this effect, with the hypoxic surgical site serving as the source of LOX. Furthermore, the lungs of recipient mice injected with plasma from post-surgical colorectal cancer patients are more prone to metastatic seeding than mice injected with baseline plasma. Downregulation of LOX activity or levels reduces lung metastasis after surgery and increases survival, highlighting the potential of LOX inhibition in reducing the risk of metastasis following surgery