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

Guorong Li, Heather Schmitt, William M. Johnson, Chanyoung Lee, Iris Navarro, Jenny Cui, Todd Fleming, María Gomez-Caraballo, Michael H. Elliott, Joseph M. Sherwood, Michael A. Hauser, Sina Farsiu, C. Ross Ethier, W. Daniel Stamer

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)10762-10777
Number of pages16
JournalFASEB Journal
Volume34
Issue number8
DOIs
StatePublished - Aug 1 2020
Externally publishedYes

Keywords

  • Schlemm's canal
  • crosslinking
  • elastin
  • extracellular matrix
  • fibrosis
  • intraocular pressure

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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