Lysyl Oxidase Is Required for Vascular and Diaphragmatic Development in Mice

Abstract

Lysyl oxidase (LOX) is an enzyme responsible for the cross-linking of collagen and elastin both in vitro and in vivo. The unique functions of the individual members of this multigene family have been difficult to ascertain because of highly conserved catalytic domains and overlapping tissue expression patterns. To address this problem of functional and structural redundancy and to determine the role of LOX in the development of tissue integrity, Lox gene expression was deleted by targeted mutagenesis in mice. Lox-targeted mice (LOX ؊/؊ ) died soon after parturition, exhibiting cardiovascular instability with ruptured arterial aneurysms and diaphragmatic rupture. Microscopic analysis of the aorta demonstrated fragmented elastic fiber architecture in homozygous mutant null mice. LOX activity, as assessed by desmosine (elastin cross-link) analysis, was reduced by ϳ60% in the aorta and lungs of homozygous mutant animals compared with wild type mice. Immature collagen cross-links were decreased but to a lesser degree than elastin cross-links in LOX ؊/؊ mice. Thus, lysyl oxidase appears critical during embryogenesis for structural stability of the aorta and diaphragm and connective tissue development.

Elastic fiber homeostasis requires lysyl oxidase–like 1 protein

“…Thus, LOXL1 seems to function primarily to guide elastin deposition in a spatially defined manner, a prerequisite for the formation of functional elastic fibers. The localization pattern of LOX, on the other hand, seems consistent with a role in cross-linking both collagens and elastin 17,18 .…”

“…LOXL1 is closely related to the prototypic LOX, and both are widely expressed. Although no difference in substrate selectivity was detected in vitro, the inability of LOX to compensate for LOXL1 and the largely nonoverlapping phenotypes of the gene-ablated mutants 17,18 are suggestive of functional differences in vivo. By immunolocalization using monospecific antibodies, LOXL1 was closely associated with the elastic lamina whereas LOX was broadly distributed (Fig.…”

“…Gene targeting studies show that fibulin-5 is required for elastic fiber development 14,16 . Disruption of the gene Lox leads to a reduction in collagen and elastin cross-links and perinatal lethality 17,18 , suggestive of a role in cross-linking both fibrillar collagens and elastin during development.…”

Neutrophil elastase-initiated EGFR/MEK/ERK signaling counteracts stabilizing effect of autocrine TGF-β on tropoelastin mRNA in lung fibroblasts

“…This finding suggests that LOX protein in chronically EGF-treated cell cultures may still be present at sites of elastogenesis in sufficient amounts. Alternatively, another possibility is that LOXL proteins might substitute for any deficiency of LOX protein (10,19). In contrast, fibrillin 1 and fibulin 5 mRNA expression levels were not decreased by EGFR/MEK/ERK signaling, implying that alterations in the levels of these elastin-associated proteins are Fig.…”

New insights into elastic fiber assembly

“…The elastic lamellae in the aorta are fragmented and discontinuous and the vessel wall is thicker with a decreased lumen size. Desmosine cross-links are reduced approximately 60% in the aorta and lungs (Maki et al, 2002;Hornstra et al, 2003). Lox2/2 mice also show impaired airway development in the lungs and abnormal collagen and elastin fibers in the skin (Maki et al, 2005).…”