Lysyl oxidase‐like 2 is a regulator of angiogenesis through modulation of endothelial‐to‐mesenchymal transition

Abstract

Lysyl oxidase‐like 2 (LOXL2) belongs to the family of lysyl oxidases, and as such promotes crosslinking of collagens and elastin by oxidative deamination of lysine residues. In endothelial cells (ECs), LOXL2 is involved in crosslinking and scaffolding of collagen IV. Additionally, several reports have shown a role for LOXL2 in other processes, including regulation of gene expression, tumor metastasis, and epithelial‐to‐mesenchymal transition (EMT). Here, we demonstrate an additional role for LOXL2 in the regulation of angiogenesis by modulation of endothelial‐to‐mesenchymal transition (EndMT). LOXL2 knockdown in ECs results in decreased migration and sprouting, and concordantly, LOXL2 overexpression leads to an increase in migration and sprouting, independent of its catalytic activity. Furthermore, LOXL2 knockdown resulted in a reduced expression of EndMT markers, and inhibition of transforming growth factor‐β (TGF‐β)‐mediated induction of EndMT. Interestingly, unlike in EMT, overexpression of LOXL2 alone is insufficient to induce EndMT. Further investigation revealed that LOXL2 expression regulates protein kinase B (PKB)/Akt and focal adhesion kinase (FAK) signaling, both pathways that have been implicated in the regulation of EMT. Altogether, our studies reveal a role for LOXL2 in angiogenesis through the modulation of EndMT in ECs, independent of its enzymatic crosslinking activity.

Lysyl Oxidase-Like Protein 2 Promotes Tumor Lymphangiogenesis and Lymph Node Metastasis in Breast Cancer

“…In 2017, professor Cano’ group used conditional transgenic mouse models to establish that LOXL2 promoted metastasis of breast cancer independent of its conventional role in extracellular matrix remodeling [46]. Furthermore, many studies showed LOXL2 has been characterized as a pro-angiogenic factor [47], [48], [49]. Nevertheless, the effects of LOXL2 on tumor lymphangiogenesis, an important prognosis predictor in breast cancer patients, have not been reported yet.…”

Emerging Roles of Lysyl Oxidases in the Cardiovascular System: New Concepts and Therapeutic Challenges

“…In fact, in models of pathological and developmental neovascularization, LOXL2 was detected in angiogenic endothelial cells and tip cells [85,86] and its knockdown in zebrafish embryos significantly suppressed intersegmental vessel circulation. Gain- and loss-of-function studies in HUVEC and microvascular endothelial cells evidenced that LOXL2 contributes to endothelial tube formation through the modulation of endothelial cell migration and proliferation [85,87], and more importantly through collagen IV network assembly, which seems to be critical for capillary formation [85]. It should be noted that in this study on cell migration, tubulogenesis and collagen IV assembly were modestly affected by BAPN, and that a catalytically inactive LOXL2 mutant triggered a similar increase in endothelial cell migration and angiogenic sprouting than wild-type LOXL2.…”

Extracellular Vesicles From Notch Activated Cardiac Mesenchymal Stem Cells Promote Myocyte Proliferation and Neovasculogenesis

“…It is expressed in neovessels as a hypoxia target and accumulated in the endothelial extracellular matrix (ECM) (Bignon et al, 2011). A gain-and-loss-of-function experiment demonstrated that LOXL-2 overexpression increased capillary formation and LOXL-2 knockdown dramatically reduced EC migration and proliferation, resulting in decreased tubulogenesis (Bignon et al, 2011;de Jong et al, 2019). In addition, biglycan overexpression in transgenic mice has been shown to induce cardioprotective genes [nitric oxide (NO) synthases] in the heart (Bereczki et al, 2007).…”