Dataset Information

Integral role for lysyl oxidase-like-1 in conventional outflow tissue function and behavior.

ABSTRACT: Lysyl oxidase-like-1 (LOXL1), a vital crosslinking enzyme in elastin fiber maintenance, is essential for the stability and strength of elastic vessels and tissues. Variants in the LOXL1 locus associate with a dramatic increase in risk of exfoliation syndrome (XFS), a systemic fibrillopathy, which often presents with ocular hypertension and exfoliation glaucoma (XFG). We examined the role of LOXL1 in conventional outflow function, the prime regulator of intraocular pressure (IOP). Using Loxl1^-/- , Loxl1^+/- , and Loxl1^+/+ mice, we observed an inverse relationship between LOXL1 expression and IOP, which worsened with age. Elevated IOP in Loxl1^-/- mice was associated with a larger globe, decreased ocular compliance, increased outflow facility, extracellular matrix (ECM) abnormalities, and dilated intrascleral veins, yet, no dilation of arteries or capillaries. Interestingly, in living Loxl1^-/- mouse eyes, Schlemm's canal (SC) was less susceptible to collapse when challenged with acute elevations in IOP, suggesting elevated episcleral venous pressure (EVP). Thus, LOXL1 expression is required for normal IOP control, while ablation results in altered ECM repair/homeostasis and conventional outflow physiology. Dilation of SC and distal veins, but not arteries, is consistent with key structural and functional roles for elastin in low-pressure vessels subjected to cyclical mechanical stress.

SUBMITTER: Li G

PROVIDER: S-EPMC7688556 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Integral role for lysyl oxidase-like-1 in conventional outflow tissue function and behavior.

Li Guorong G Schmitt Heather H Johnson William M WM Lee Chanyoung C Navarro Iris I Cui Jenny J Fleming Todd T Gomez-Caraballo María M Elliott Michael H MH Sherwood Joseph M JM Hauser Michael A MA Farsiu Sina S Ethier C Ross CR Stamer W Daniel WD

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20200705 8

Lysyl oxidase-like-1 (LOXL1), a vital crosslinking enzyme in elastin fiber maintenance, is essential for the stability and strength of elastic vessels and tissues. Variants in the LOXL1 locus associate with a dramatic increase in risk of exfoliation syndrome (XFS), a systemic fibrillopathy, which often presents with ocular hypertension and exfoliation glaucoma (XFG). We examined the role of LOXL1 in conventional outflow function, the prime regulator of intraocular pressure (IOP). Using Loxl1<sup ...[more]

PMID: 32623782

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Project description:The primary source of strength in menisci, tendons, and ligaments are hierarchical collagen fibers; however, these fibers are not regenerated after injury nor in engineered replacements, resulting in limited repair options. Collagen strength is reliant on fiber alignment, density, diameter, and crosslinking. Recently, we developed a culture system which guides cells in high-density collagen gels to develop native-like hierarchically organized collagen fibers, which match native fiber alignment and diameters by 6 weeks. However, tensile moduli plateau at 1MPa, suggesting crosslinking may be lacking. Collagen crosslinking is regulated by lysyl oxidase (LOX) which forms immature crosslinks that condense into mature trivalent crosslinks. Trivalent crosslinks are thought to be the primarily source of strength in fibers, but it's not well understood how they form. The objective of this study was to evaluate the effect of exogenous LOX in our culture system at different stages of hierarchical fiber formation to produce stronger replacements and to better understand factors affecting crosslink maturation. We found treatment with LOX isoform LOXL2 did not restrict hierarchical fiber formation, with constructs still forming aligned collagen fibrils by 2 weeks, larger fibers by 4 weeks, and early fascicles by 6 weeks. However, LOXL2 treatment did significantly increase mature pyridinium (PYD) crosslink accumulation and tissue mechanics, with timing of LOXL2 supplementation during fiber formation having a significant effect. Overall, we found one week of LOXL2 supplementation at 4 weeks produced constructs with native-like fiber organization, increased PYD accumulation, and increased mechanics, ultimately matching the tensile modulus of immature bovine menisci. STATEMENT OF SIGNIFICANCE: Collagen fibers are the primary source of strength and function in connective tissues throughout the body, however it remains a challenge to develop these fibers in engineered replacements, greatly reducing treatment options. Here we demonstrate lysyl oxidase like 2 (LOXL2) can be used to significantly improve the mechanics of tissue engineered constructs, but timing of application is important and will most likely depend on degree of collagen organization or maturation. Currently there is limited understanding of how collagen crosslinking is regulated, and this system is a promising platform to further investigate cellular regulation of LOX crosslinking. Understanding the mechanism that regulates LOX production and activity is needed to ultimately regenerate functional repair or replacements for connective tissues throughout the body.

Dataset Information

Integral role for lysyl oxidase-like-1 in conventional outflow tissue function and behavior.

Publications

Integral role for lysyl oxidase-like-1 in conventional outflow tissue function and behavior.

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