Abstract Body: Background and Objective: Aortic stiffness is a significant risk factor for cardiovascular diseases like hypertension and atherosclerosis. Vascular smooth muscle cells (SMCs) play a crucial role in maintaining aortic structural integrity, and increased SMC stiffness and extracellular matrix deposition contribute to aortic stiffness. During aortic development, lysyl oxidase (LOX) covalently crosslinks elastin and collagen to create an insoluble extracellular matrix resistant to proteolytic degradation. In this study, we aimed to examine the contribution of SMC-derived LOX to aortic stiffness development in mice.
Methods and Results: To investigate the role of SMC-LOX in aortic stiffness, mice with inducible SMC-LOX deletion were generated by breeding male mice hemizygous for Acta2-CreERT2 to female LOX floxed mice. At 8 weeks of age, male and female LOX x Acta Cre ERT2 (Cre+) and non-Cre littermates (Cre-) mice were injected with tamoxifen (75 mg/kg, i.p.) for 5 consecutive days. After 2 weeks of tamoxifen-induced cre recombination, to study the role of SMC-LOX in aortic stiffness, male Cre+, and Cre- (N=5-12 per group) were infused subcutaneously with AngII (1,000 ng/kg/min) or saline by osmotic mini-pumps for 4 weeks. Interestingly, LOX deficiency in SMCs spontaneously but significantly accelerated aortic stiffness in saline-infused mice compared to Cre- controls as evidenced by decreased aortic distensibility (Saline Cre-:123.7 ± 6.5 vs Saline Cre+: 94.6 ± 5.9; P=0.008) and radial strain (Saline Cre-:22.4 ± 1.6 vs Saline Cre+:15.9 ± 1.2; P<0.05), which are the hallmarks of aortic stiffness as measured by ultrasound. AngII infusion had no further influence on aortic stiffness (Distensibility: AngII Cre+:88.49 ± 4.5 vs Saline Cre+: 94.6 ± 5.9; P=0.4; Radial Strain: AngII Cre+:14.5 ± 0.9 vs Saline Cre+:15.9 ± 1.2; P=0.4 ) in SMC-LOX deficient mice, whereas AngII infusion significantly decreased aortic stiffness in Cre- control mice (Distensibility: AngII Cre-:77.0 ± 3.4 vs Saline Cre-:123.7 ± 6.5; P<0.001; Radial Strain: AngII Cre-12.2 ± 0.6 vs Saline Cre-:22.4 ± 1.6; P<0.001). LOX depletion in SMCs did not influence systolic blood pressures during AngII infusion. Histological analyses indicated increased elastin breaks in SMC-LOX deficiency mice compared to control mice.
Conclusion: These findings suggest that SMC-derived LOX plays a critical role in suppressing aortic stiffness in mice.