Apelin expression deficiency in mice contributes to vascular stiffening by extracellular matrix remodeling of the aortic wall

Abstract

Numerous recent studies have shown that in the continuum of cardiovascular diseases, the measurement of arterial stiffness has powerful predictive value in cardiovascular risk and mortality and that this value is independent of other conventional risk factors, such as age, cholesterol levels, diabetes, smoking, or average blood pressure. Vascular stiffening is often the main cause of arterial hypertension (AHT), which is common in the presence of obesity. However, the mechanisms leading to vascular stiffening, as well as preventive factors, remain unclear. The aim of the present study was to investigate the consequences of apelin deficiency on the vascular stiffening and wall remodeling of aorta in mice. This factor freed by visceral adipose tissue, is known for its homeostasic role in lipid and vascular metabolisms, or again in inflammation. We compared the level of metabolic markers, inflammation of white adipose tissue (WAT), and aortic wall remodeling from functional and structural approaches in apelin-deficient and wild-type (WT) mice. Apelin-deficient mice were generated by knockout of the apelin gene (APL-KO). From 8 mice by groups, aortic stiffness was analyzed by pulse wave velocity measurements and by characterizations of collagen and elastic fibers. Mann–Whitney statistical test determined the significant data (p < 5%) between groups. The APL-KO mice developed inflammation, which was associated with significant remodeling of visceral WAT, such as neutrophil elastase and cathepsin S expressions. In vitro, cathepsin S activity was detected in conditioned medium prepared from adipose tissue of the APL-KO mice, and cathepsin S activity induced high fragmentations of elastic fiber of wild-type aorta, suggesting that the WAT secretome could play a major role in vascular stiffening. In vivo, remodeling of the extracellular matrix (ECM), such as collagen accumulation and elastolysis, was observed in the aortic walls of the APL-KO mice, with the latter associated with high cathepsin S activity. In addition, pulse wave velocity (PWV) and AHT were increased in the APL-KO mice. The latter could explain aortic wall remodeling in the APL-KO mice. The absence of apelin expression, particularly in WAT, modified the adipocyte secretome and facilitated remodeling of the ECM of the aortic wall. Thus, elastolysis of elastic fibers and collagen accumulation contributed to vascular stiffening and AHT. Therefore, apelin expression could be a major element to preserve vascular homeostasis.

Effects of Long-Term Intervention with Losartan, Aspirin and Atorvastatin on Vascular Remodeling in Juvenile Spontaneously Hypertensive Rats

“…If hypertension is not managed in adolescents, it can continue into adulthood and old age. Therefore, in our study, five-week-old SHRs whose blood pressure rises gradually were selected as the animal model for adolescents hypertension [ 32 ], and losartan, aspirin, and atorvastatin were administered at the age of 6 weeks. After long-term intervention, the effects on vascular remodeling were observed at the age of 22 weeks.…”

“…Autofluorescence of elastic fibers in tissue sections stained H&E was recorded with excitation wavelength at 460 nm–550 nm (Olympus 1 × 2 UCB) [ 32 , 82 ].…”

Connecting Aortic Stiffness to Vascular Contraction: Does Sex Matter?

“…Aortic rings (10 m) from both sexes were excited at 488 nm with equal exposure time [ 44 ]. Autofluorescence values are reported as arbitrary units, which were computed with the ImageJ software in images without the background (4× magnification).…”

“…Number of laminae was manually evaluated, and is reported as the average of independent measurements across three regions (top, middle, bottom) of the image. Number of elastin fragments were determined with the threshold function in the ImageJ software (10× magnification) [ 44 ]. Representative images were modified for brightness and contrast using the same parameters.…”

Stiffening Matrix Induces Age‐Mediated Microvascular Phenotype Through Increased Cell Contractility and Destabilization of Adherens Junctions

“…[ 21 ] Specifically, in vivo evidence indicates that increased ECM stiffness in large vessels, such as arteries, might contribute to vascular dysfunction and diseases like hypertension and atherosclerosis. [ 25 , 26 , 27 ] In these large vessels, an increase in collagen deposition in the vessels’ walls and the subsequent changes in their mechanical properties can have fatal effects on endothelial cell (EC) function via mechano‐sensitive signaling pathways. [ 28 , 29 ] Previous studies further suggested that an increase in ECM stiffness influences the vascular morphology in tumor vessels leading to a leaky vascular phenotype.…”