Inactivation of the Lysyl Oxidase Gene Lox Leads to Aortic Aneurysms, Cardiovascular Dysfunction, and Perinatal Death in Mice

Abstract

Background-The lysyl oxidases are extracellular copper enzymes that initiate the crosslinking of collagens and elastin, 5 human isoenzymes having been characterized so far. The crosslinks formed provide the tensile strength and elastic properties for various extracellular matrices, including vascular walls. We studied the role of the first described isoenzyme Lox by inactivating its gene in mice. Methods and Results-Murine Lox gene was disrupted by routine methods. Lox Ϫ/Ϫ mice died at the end of gestation or as neonates, necropsy of the live-born pups revealing large aortic aneurysms. In light microscopy, hazy and unruffled elastic lamellae in the Lox Ϫ/Ϫ aortas were observed, and electron microscopy of the aortic walls of the Lox Ϫ/Ϫ fetuses showed highly fragmented elastic fibers and discontinuity in the smooth muscle cell layers in Lox Ϫ/Ϫ fetuses. The wall of the aorta in the Lox Ϫ/Ϫ fetuses was significantly thicker, and the diameter of the aortic lumen was significantly smaller than that in the Lox ϩ/ϩ aortas. In Lox Ϫ/Ϫ fetuses, Doppler ultrasonography revealed increased impedance in the umbilical artery, descending aorta, and intracranial artery blood velocity waveforms, decreased mean velocities across cardiac inflow and outflow regions, and increased pulsatility in ductus venosus blood velocity waveforms. Conclusions-Lox

Vascular smooth muscle cells direct extracellular dysregulation in aortic stiffening of hypertensive rats

“…This may be due to the reduced extracellular release of LOX from SHR TA VSMCs. The decrease in extracellular LOX activity in SHR TA VSMC support previous studies showing LOX deficiency causes disorganized connective tissue formation in vivo (Lee et al., 2016; Maki et al., 2002; Staiculescu et al., 2017) and may also explain the disorganization of collagen observed in the reconstituted tissue with SHR TA VSMCs.…”

“…For example, while it has been shown that the downregulation of LOX contributes to the aortic stiffening in an obesity mouse model (Chen et al., 2013), other studies have shown that inhibition of LOX attenuated the angiotensin II induced aortic stiffening (Eberson et al., 2015). In addition, as evidence showed that genetic deletion or functional deficiency of LOX causes aortic wall destruction and leads to aortic stiffening (Lee et al., 2016; Maki et al., 2002; Staiculescu et al., 2017), a smooth muscle cell‐specific overexpression of LOX in a mouse model has been shown to induces arterial stiffness (Martinez‐Revelles et al., 2017). Although the reasons for these inconsistencies are unclear, one potential explanation may arise from the distinct extracellular and intracellular effects of LOX.…”

“…For example, downregulation of LOX has been associated with destructive remodeling of arteries during aorta aneurysm (AA) development (Yoshimura et al., 2006). Deletion of the mouse LOX gene promotes fragmentation of elastic fibers and VSMC discontinuity in the aortic wall, leading to increased impedance and a predisposition to thoracic AAs and dissections (Maki et al., 2002; Staiculescu, Kim, Mecham & Wagenseil, 2017). Loss‐of‐function mutations of LOX can cause AAs and aortic stiffening in humans (Lee et al., 2016).…”

Elastic fiber homeostasis requires lysyl oxidase–like 1 protein

“…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.…”