Adrenomedullin induces matrix metalloproteinase-2 activity in rat aortic adventitial fibroblasts

Background

The delicate balance of the extracellular matrix (ECM) determines the stiffness of the vascular wall, and adventitial fibroblasts are involved in ECM formation by synthesizing and degrading matrix proteins. In the present study, we examined the effect of the bioactive peptide adrenomedullin (AM) on activity and expression of matrix metalloproteinases (MMPs) in cultured aortic adventitial fibroblasts.

Methods and results

In cultured adventitial fibroblasts isolated from aorta of adult Wistar rats, 10⁻⁶ mol/L angiotensin II (Ang II) significantly (p < 0.05) down-regulated MMP-2 activity as determined by in vitro gelatin zymography. In contrast, 10⁻⁷ mol/L synthetic rat AM significantly (p < 0.05) stimulated zymographic MMP-2 activity by 23%, increasing intracellular cAMP, and AM abolished the action of Ang II, augmenting the MMP-2 activity. Similarly, Ang II down-regulated MMP-2 protein expression assessed by Western blotting, whereas AM increased it. Furthermore, 8-bromo-cAMP, an analogue of cAMP, mimicked the effect of AM, and H-89, an inhibitor for protein kinase A (PKA), significantly decreased the basal and AM-induced MMP-2 activity.

Conclusion

This study provides a new insight into the biological action of AM and its intracellular signaling system of cAMP/PKA stimulating the matrix degrading enzyme MMP-2, suggesting an important role for this molecule in modulating ECM deposition in the adventitial layer.     

The Lysyl Oxidase Inhibitor, β-Aminopropionitrile,Diminishes the Metastatic Colonization Potential of Circulating Breast Cancer Cells

Lysyl oxidase (LOX), an extracellular matrix remodeling enzyme, appears to have a role in promoting breast cancer cell motility and invasiveness. In addition, increased LOX expression has been correlated with decreases in both metastases-free, and overall survival in breast cancer patients. With this background, we studied the ability of β-aminopropionitrile (BAPN), an irreversible inhibitor of LOX, to regulate the metastatic colonization potential of the human breast cancer cell line, MDA-MB-231. BAPN was administered daily to mice starting either 1 day prior, on the same day as, or 7 days after intracardiac injection of luciferase expressing MDA-MB-231-Luc2 cells. Development of metastases was monitored by in vivo bioluminescence imaging, and tumor-induced osteolysis was assessed by micro-computed tomography (μCT). We found that BAPN administration was able to reduce the frequency of metastases. Thus, when BAPN treatment was initiated the day before, or on the same day as the intra-cardiac injection of tumor cells, the number of metastases was decreased by 44%, and 27%, and whole-body photon emission rates (reflective of total tumor burden) were diminished by 78%, and 45%, respectively. In contrast, BAPN had no effect on the growth of established metastases. Our findings suggest that LOX activity is required during extravasation and/or initial tissue colonization by circulating MDA-MB-231 cells, lending support to the idea that LOX inhibition might be useful in metastasis prevention.     

Rosiglitzone Suppresses Angiotensin II-Induced Production of KLF5 and Cell Proliferation in Rat Vascular Smooth Muscle Cells

Krüppel-like factor (KLF) 5, which initiates vascular smooth muscle cell (VSMC) proliferation, also participates in Angiotensin (Ang) II-induced vascular remodeling. The protective effect of rosiglitazone on vascular remodeling may be due to their impact on VSMC proliferation. However, the underlying mechanisms involved remain unclear. This study was designed to investigate whether the antiproliferation effects of rosiglitazone are mediated by regulating Ang II/KLF5 response. We found that, in aortas of Ang II-infused rats, vascular remodeling and KLF5 expression were markedly increased, and its target gene cyclin D1 was overexpressed. Co-treatment with rosiglitazone diminished these changes. In growth-arrested VSMCs, PPAR-γ agonists (rosiglitazone and 15d-PGJ2) dose-dependently inhibited Ang II-induced cell proliferation and expression of KLF5 and cyclin D1. Moreover, these effects were attenuated by the PPAR-γ antagonists GW9662, bisphenol A diglycidyl ether and PPAR-γ specific siRNA. Furthermore, rosiglitazone inhibited Ang II-induced phosphorylation of protein kinase C (PKC) ζ and extracellular signal-regulated kinase (ERK) 1/2 and activation of early growth response protein (Egr). In conclusion, in Ang II-stimulated VSMCs, rosiglitazone might have an antiproliferative effect through mechanisms that include reducing KLF5 expression, and a crosstalk between PPAR-γ and PKCζ/ERK_1/2/Egr may be involved in. These findings not only provide a previously unrecognized mechanism by which PPAR-γ agonists inhibit VSMC proliferation, but also document a novel evidence for the beneficial vascular effect of PPAR-γ activation.     

T-lymphocytes mediate left ventricular fibrillar collagen cross-linking and diastolic dysfunction in mice

Aberrant concentrations of cardiac extracellular matrix (ECM) fibrillar collagen cross-linking have been proposed to be an underlying cause of cardiac diastolic dysfunction however the role of the adaptive immune system in this process has yet to be investigated. Fibrillar collagen cross-linking is a product of the enzymatic activities of lysyl oxidase (LOX and LOXL-3) released by the cardiac fibroblast and possibly cardiac myocytes. Our hypothesis is that stimulation of the TH1 lymphocytes activates lysyl oxidase mediated ECM cross-linking and thereby alters left ventricular function. Three-month old C57BL/J female mice were treated with selective TH1 lymphocyte inducers — T-cell receptor Vβ peptides (TCR). After 6 weeks, candidate gene expression, tissue enzymatic activity, ECM composition, and left ventricular mechanics were quantified. Lymphocyte gene expression and cytokine assay revealed TH1 immune polarization with TCR administration which was associated with a 2.6-fold and 3.1-fold increase of LOX and LOXL3 gene expression, respectively, and a 55% increase in cardiac LOX enzymatic activity. The ECM cross-linked fibrillar collagen increased by 95% when compared with the control. Concurrently, there was a 33% increased ventricular stiffness, decreased cardiac output, and normal ejection fraction. These data implicate the TH1 lymphocyte in the pathogenesis of diastolic dysfunction which has potential clinical application in the pathogenesis of diastolic heart failure.     

A Food-Derived Flavonoid Luteolin Protects against Angiotensin II-Induced Cardiac Remodeling

Oxidative stress has been implicated in cardiac remodeling (cardiac fibrosis and hypertrophy), which impairs cardiac function and metabolism; therefore, it is anticipated antioxidative compounds will have protective properties against cardiac remodeling. Luteolin (3’,4’,5,7-tetrahydroxyflavone), a widely distributed flavonoid found in many herbal extracts including celery, green pepper, perilla leaves and seeds, and chamomile, is a known to be a potent antioxidant and was previously demonstrated to exert an antifibrotic effect in the lungs and the liver. In this study, we clearly demonstrate that oral pretreatment with the higher-luteolin diet (0.035% (wt/wt)) protected against cardiac fibrosis and hypertrophy as well as a hyperoxidative state in Ang II-infused rats. In cardiac tissue, increased gene expression levels of TGFβ1, CTGF, Nox2, Nox4, ANP, and BNP induced by Ang II were restored by oral pretreatment of this high-luteolin diet. In cultured rat cardiac fibroblasts, H₂O₂-induced TGFβ1 expression and the phosphorylation of JNK were suppressed by luteolin pretreatment. In conclusion, food-derived luteolin has protective actions against Ang II-induced cardiac remodeling, which could be mediated through attenuation of oxidative stress.     

Aortic and Carotid Arterial Stiffness and Epigenetic Regulator Gene Expression Changes Precede Blood Pressure Rise in Stroke-Prone Dahl Salt-Sensitive Hypertensive Rats

Multiple clinical studies show that arterial stiffness, measured as pulse wave velocity (PWV), precedes hypertension and is an independent predictor of hypertension end organ diseases including stroke, cardiovascular disease and chronic kidney disease. Risk factor studies for arterial stiffness implicate age, hypertension and sodium. However, causal mechanisms linking risk factor to arterial stiffness remain to be elucidated. Here, we studied the causal relationship of arterial stiffness and hypertension in the Na-induced, stroke-prone Dahl salt-sensitive (S) hypertensive rat model, and analyzed putative molecular mechanisms. Stroke-prone and non-stroke-prone male and female rats were studied at 3- and 6-weeks of age for arterial stiffness (PWV, strain), blood pressure, vessel wall histology, and gene expression changes. Studies showed that increased left carotid and aortic arterial stiffness preceded hypertension, pulse pressure widening, and structural wall changes at the 6-week time-point. Instead, differential gene induction was detected implicating molecular-functional changes in extracellular matrix (ECM) structural constituents, modifiers, cell adhesion, and matricellular proteins, as well as in endothelial function, apoptosis balance, and epigenetic regulators. Immunostaining testing histone modifiers Ep300, HDAC3, and PRMT5 levels confirmed carotid artery-upregulation in all three layers: endothelial, smooth muscle and adventitial cells. Our study recapitulates observations in humans that given salt-sensitivity, increased Na-intake induced arterial stiffness before hypertension, increased pulse pressure, and structural vessel wall changes. Differential gene expression changes associated with arterial stiffness suggest a molecular mechanism linking sodium to full-vessel wall response affecting gene-networks involved in vascular ECM structure-function, apoptosis balance, and epigenetic regulation.     

Angiotensin II downregulates catalase expression and activity in vascular adventitial fibroblasts through an AT1R/ERK1/2-dependent pathway

Angiotensin II (Ang II) plays a profound regulatory effect on NADPH oxidase and the functional features of vascular adventitial fibroblasts, but its role in antioxidant enzyme defense remains unclear. This study investigated the effect of Ang II on expressions and activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) in adventitial fibroblasts and the possible mechanism involved. Ang II decreased the expression and activity of CAT in a dose- and time-dependent manner, but not that of SOD and GPx. The effects were abolished by the angiotensin II type 1 receptor (AT1R) blocker losartan and AT1R small-interfering RNA (siRNA). Incubation with polyethylene glycol-CAT prevented the Ang II-induced effects on reactive oxygen species (ROS) generation and myofibroblast differentiation. Moreover, Ang II rapidly induced phosphorylation of ERK1/2, which was reversed by losartan and AT1R siRNA. Pharmacological blockade of ERK1/2 improved Ang II-induced decrease in CAT protein expression. These in vitro results indicate that Ang II induces ERK1/2 activation, contributing to the downregulation of CAT as well as promoting oxidative stress and adventitial fibroblast phenotypic differentiation in an AT1R-mediated manner.     

Reliability and Validity of Quantifying Absolute Muscle Hardness Using Ultrasound Elastography

Muscle hardness is a mechanical property that represents transverse muscle stiffness. A quantitative method that uses ultrasound elastography for quantifying absolute human muscle hardness has been previously devised; however, its reliability and validity have not been completely verified. This study aimed to verify the reliability and validity of this quantitative method. The Young’s moduli of seven tissue-mimicking materials (in vitro; Young’s modulus range, 20–80 kPa; increments of 10 kPa) and the human medial gastrocnemius muscle (in vivo) were quantified using ultrasound elastography. On the basis of the strain/Young’s modulus ratio of two reference materials, one hard and one soft (Young’s moduli of 7 and 30 kPa, respectively), the Young’s moduli of the tissue-mimicking materials and medial gastrocnemius muscle were calculated. The intra- and inter-investigator reliability of the method was confirmed on the basis of acceptably low coefficient of variations (≤6.9%) and substantially high intraclass correlation coefficients (≥0.77) obtained from all measurements. The correlation coefficient between the Young’s moduli of the tissue-mimicking materials obtained using a mechanical method and ultrasound elastography was 0.996, which was equivalent to values previously obtained using magnetic resonance elastography. The Young’s moduli of the medial gastrocnemius muscle obtained using ultrasound elastography were within the range of values previously obtained using magnetic resonance elastography. The reliability and validity of the quantitative method for measuring absolute muscle hardness using ultrasound elastography were thus verified.     

Role of collagen content and cross-linking in large pulmonary arterial stiffening after chronic hypoxia

Chronic hypoxic pulmonary hypertension (HPH) is associated with large pulmonary artery (PA) stiffening, which is correlated with collagen accumulation. However, the mechanisms by which collagen contributes to PA stiffening remain largely unexplored. Moreover, HPH may alter mechanical properties other than stiffness, such as pulse damping capacity, which also affects ventricular workload but is rarely quantified. We hypothesized that collagen content and cross-linking differentially regulate the stiffness and damping capacity of large PAs during HPH progression. The hypothesis was tested with transgenic mice that synthesize collagen type I resistant to collagenase degradation (Col1a1(R/R)). These mice and littermate controls (Col1a1(+/+)) were exposed to hypoxia for 10 days; some were treated with β-aminopropionitrile (BAPN), which prevents new cross-link formation. Isolated PA dynamic mechanical tests were performed, and collagen content and cross-linking were measured. In Col1a1(+/+) mice, HPH increased both collagen content and cross-linking, and BAPN treatment prevented these increases. Similar trends were observed in Col1a1(R/R) mice except that collagen content further increased with BAPN treatment. Mechanical tests showed that in Col1a1(+/+) mice, HPH increased PA stiffness and damping capacity, and these increases were impeded by BAPN treatment. In Col1a1(R/R) mice, HPH led to a smaller but significant increase in PA stiffness and a decrease in damping capacity. These mechanical changes were not affected by BAPN treatment. Vessel-specific correlations for each strain showed that the stiffness and damping capacity were correlated with the total content rather than cross-linking of collagen. Our results suggest that collagen total content is critical to extralobar PA stiffening during HPH.     

Loss of Timp3 Gene Leads to Abdominal Aortic Aneurysm Formation in Response to Angiotensin II

Aortic aneurysm is dilation of the aorta primarily due to degradation of the aortic wall extracellular matrix (ECM). Tissue inhibitors of metalloproteinases (TIMPs) inhibit matrix metalloproteinases (MMPs), the proteases that degrade the ECM. Timp3 is the only ECM-bound Timp, and its levels are altered in the aorta from patients with abdominal aortic aneurysm (AAA). We investigated the causal role of Timp3 in AAA formation. Infusion of angiotensin II (Ang II) using micro-osmotic (Alzet) pumps in Timp3^−/− male mice, but not in wild type control mice, led to adverse remodeling of the abdominal aorta, reduced collagen and elastin proteins but not mRNA, and elevated proteolytic activities, suggesting excess protein degradation within 2 weeks that led to formation of AAA by 4 weeks. Intriguingly, despite early up-regulation of MMP2 in Timp3^−/−Ang II aortas, additional deletion of Mmp2 in these mice (Timp3^−/−/Mmp2^−/−) resulted in exacerbated AAA, compromised survival due to aortic rupture, and inflammation in the abdominal aorta. Reconstitution of WT bone marrow in Timp3^−/−/Mmp2^−/− mice reduced inflammation and prevented AAA in these animals following Ang II infusion. Treatment with a broad spectrum MMP inhibitor (PD166793) prevented the Ang II-induced AAA in Timp3^−/− and Timp3^−/−/Mmp2^−/− mice. Our study demonstrates that the regulatory function of TIMP3 is critical in preventing adverse vascular remodeling and AAA. Hence, replenishing TIMP3, a physiological inhibitor of a number of metalloproteinases, could serve as a therapeutic approach in limiting AAA development or expansion.     

Src Family Kinases (SFK) Mediate Angiotensin II-Induced Myosin Light Chain Phosphorylation and Hypertension

Angiotensin (Ang) II is the major bioactive peptide of the renin–angiotensin system (RAS); it contributes to the pathogenesis of hypertension by inducing vascular contraction and adverse remodeling, thus elevated peripheral resistance. Ang II also activates Src family kinases (SFK) in the vascular system, which has been implicated in cell proliferation and migration. However, the role of SFK in Ang II-induced hypertension is largely unknown. In this study, we found that administration of a SFK inhibitor SU6656 markedly lowered the level of systemic BP in Ang II-treated mice, which was associated with an attenuated phosphorylation of the smooth-muscle myosin-light-chain (MLC) in the mesenteric resistant arteries. In the cultured human coronary artery smooth muscle cells (SMCs), pretreatment with SU6656 blocked Ang II-induced MLC phosphorylation and contraction. These results for the first time demonstrate that SFK directly regulate vascular contractile machinery to influence BP. Thus our study provides an additional mechanistic link between Ang II and vasoconstriction via SFK-enhanced MLC phosphorylation in SMCs, and suggests that targeted inhibition of Src may provide a new therapeutic opportunity in the treatment of hypertension.     

Lysyl Oxidase Activity Is Required for Ordered Collagen Fibrillogenesis by Tendon Cells

Lysyl oxidases (LOXs) are a family of copper-dependent oxido-deaminases that can modify the side chain of lysyl residues in collagen and elastin, thereby leading to the spontaneous formation of non-reducible aldehyde-derived interpolypeptide chain cross-links. The consequences of LOX inhibition in producing lathyrism are well documented, but the consequences on collagen fibril formation are less clear. Here we used β-aminoproprionitrile (BAPN) to inhibit LOX in tendon-like constructs (prepared from human tenocytes), which are an experimental model of cell-mediated collagen fibril formation. The improvement in structure and strength seen with time in control constructs was absent in constructs treated with BAPN. As expected, BAPN inhibited the formation of aldimine-derived cross-links in collagen, and the constructs were mechanically weak. However, an unexpected finding was that BAPN treatment led to structurally abnormal collagen fibrils with irregular profiles and widely dispersed diameters. Of special interest, the abnormal fibril profiles resembled those seen in some Ehlers-Danlos Syndrome phenotypes. Importantly, the total collagen content developed normally, and there was no difference in COL1A1 gene expression. Collagen type V, decorin, fibromodulin, and tenascin-X proteins were unaffected by the cross-link inhibition, suggesting that LOX regulates fibrillogenesis independently of these molecules. Collectively, the data show the importance of LOX for the mechanical development of early collagenous tissues and that LOX is essential for correct collagen fibril shape formation.     

Expression and function of osteopontin in vascular adventitial fibroblasts and pathological vascular remodeling

Osteopontin is known to play important roles in various diseases including vascular disorders. However, little is known about its expression and function in vascular adventitial fibroblasts. Adventitial fibroblasts have been shown to play a key role in pathological vascular remodeling associating with various vascular disorders. In this study, we measured activation of Osteopontin and its biological functions in cultured adventitial fibroblasts and injured rat carotid injury arteries induced by balloon angioplasty. Our results showed that angiotensin II and aldosterone increased Osteopontin expression in adventitial fibroblasts in a time- and concentration-dependent manner. MAPKs and AP-1 pathways were involved in Osteopontin upregulation. In addition, Adventitial fibroblast migration stimulated by Angiotensin II and aldosterone required OPN expression. Perivascular delivery of antisense oligonucleotide for Osteopontin suppressed neointimal formation post-injury. We concluded that upregulation of Osteopontin expression in adventitial fibroblasts might be important in the pathogenesis of vascular remodeling after arterial injury.     

Tumor Necrosis Factor - Alpha Is Essential for Angiotensin II-Induced Ventricular Remodeling: Role for Oxidative Stress

The functional crosstalk between angiotensin II (Ang II) and tumor necrosis factor (TNF)-α has been shown to cause adverse left ventricular remodeling and hypertrophy in hypertension. Previous studies from our lab showed that mice lacking TNF-α (TNF-α^-/-) have attenuated hypertensive response to Ang II; however, the signaling mechanisms involved are not known. In this study, we investigated the signaling pathways involved in the Ang II and TNF-α interaction. Chronic Ang II infusion (1μg/kg/min, 14 days) significantly increased cardiac collagen I, collagen III, CTGF and TGF-β mRNA and protein expression in wild-type (WT) mice, whereas these changes were decreased in TNF-α^-/- mice. TNF-α^-/- mice with Ang II infusion showed reduced myocardial perivascular and interstitial fibrosis compared to WT mice with Ang II infusion. In WT mice, Ang II infusion increased reactive oxygen species formation and the expression of NADPH oxidase subunits, indicating increased oxidative stress, but not in TNF-α^-/- mice. In addition, treatment with etanercept (8 mg/kg, every 3 days) for two weeks blunted the Ang II-induced hypertension (133±4 vs 154±3 mmHg, p<0.05) and cardiac hypertrophy (heart weight to body weight ratio, 4.8±0.2 vs 5.6±0.3, p<0.05) in WT mice. Furthermore, Ang II-induced activation of NF-κB, p38 MAPK, and JNK were reduced in both TNF-α^-/- mice and mice treated with etanercept. Together, these findings indicate that TNF-α contributes to Ang II-induced hypertension and adverse cardiac remodeling, and that these effects are associated with changes in the oxidative stress dependent MAPK/TGF-β/NF-κB pathway. These results may provide new insight into the mechanisms of Ang II and TNF-α interaction.     

Increased Rate of Arterial Stiffening with Obesity in Adolescents: A Five-Year Follow-Up Study

Background

We prospectively and longitudinally determined the effects of childhood obesity on arterial stiffening and vascular wall changes. Changes in arterial stiffness measured as pulse wave velocity (PWV) and vascular morphology of the radial (RA) and dorsal pedal arteries (DPA) were examined in obese adolescents compared to lean subjects in a 5-year follow-up study.

Methodology/Principal Findings

A total of 28 obese subjects and 14 lean controls participated in both baseline (14 years old) and follow-up studies. PWV was measured by tonometer (SphygmoCor®) and recorded at RA and carotid artery, respectively. Intima thickness (IT), intima-media thickness (IMT) and RA and DPA diameters were measured using high-resolution ultrasound (Vevo 770™). Over the course of 5 years, PWV increased by 25% in the obese subjects as compared to 3% in the controls (p = 0.01). Diastolic blood pressure (DBP) increased by 23% in the obese subjects as opposed to 6% in controls (p = 0.009). BMI increased similarly in both groups, as did the IT and IMT. The change in PWV was strongly associated to the baseline BMI z -score (r = 0.51, p<0.001), as was the change in DBP (r = 0.50, p = 0.001).

Conclusions/Significance

During the transition from early to late adolescence, there was a general increase in arterial stiffness, which was aggravated by childhood obesity. The increase in arterial stiffness and DBP after 5 years was closely correlated to the baseline BMI z -score, indicating that childhood obesity has an adverse impact on vascular adaptation.     

Folic Acid Mitigates Angiotensin-II-Induced Blood Pressure and Renal Remodeling

Clinical data suggests an association between systolic hypertension, renal function and hyperhomocysteinemia (HHcy). HHcy is a state of elevated plasma homocysteine (Hcy) levels and is known to cause vascular complications. In this study, we tested the hypothesis whether Ang II-induced hypertension increases plasma Hcy levels and contributes to renovascular remodeling. We also tested whether folic acid (FA) treatment reduces plasma Hcy levels by enhancing Hcy remethylation and thus mitigating renal remodeling. Hypertension was induced in WT mice by infusing Ang II using Alzet mini osmotic pumps. Blood pressure, Hcy level, renal vascular density, oxidative stress, inflammation and fibrosis markers, and angiogenic- and anti-angiogenic factors were measured. Ang II hypertension increased plasma Hcy levels and reduced renal cortical blood flow and microvascular density. Elevated Hcy in Ang II hypertension was associated with decreased 4, 5-Diaminofluorescein (DAF-2DA) staining suggesting impaired endothelial function. Increased expression of Nox-2, -4 and dihydroethidium stain revealed oxidative stress. Excess collagen IV deposition in the peri-glomerular area and increased MMP-2, and -9 expression and activity indicated renal remodeling. The mRNA and protein expression of asymmetric dimethylarginine (ADMA) was increased and eNOS protein was decreased suggesting the involvement of this pathway in Hcy mediated hypertension. Decreased expressions of VEGF and increased anti-angiogenic factors, angiostatin and endostatin indicated impaired vasculogenesis. FA treatment partially reduced hypertension by mitigating HHcy in Ang II-treated animals and alleviated pro-inflammatory, pro-fibrotic and anti-angiogenic factors. These results suggest that renovascular remodeling in Ang II-induced hypertension is, in part, due to HHcy.     

MiR‐126a‐5p limits the formation of abdominal aortic aneurysm in mice and decreases ADAMTS‐4 expression

Abdominal aortic aneurysm (AAA) is a serious vascular disease featured by inflammatory infiltration in aortic wall, aortic dilatation and extracellular matrix (ECM) degradation. Dysregulation of microRNAs (miRNAs) is implicated in AAA progress. By profiling miRNA expression in mouse AAA tissues and control aortas, we noted that miR‐126a‐5p was down‐regulated by 18‐fold in AAA samples, which was further validated with real‐time qPCR. This study was performed to investigate miR‐126a‐5p's role in AAA formation. In vivo, a 28‐d infusion of 1 μg/kg/min Angiotensin (Ang) II was used to induce AAA formation in Apoe^‐/‐ mice. MiR‐126a‐5p (20 mg/kg; MIMAT0000137) or negative control (NC) agomirs were intravenously injected to mice on days 0, 7, 14 and 21 post‐Ang II infusion. Our data showed that miR‐126a‐5p overexpression significantly improved the survival and reduced aortic dilatation in Ang II‐infused mice. Elastic fragment and ECM degradation induced by Ang II were also ameliorated by miR‐126a‐5p. A strong up‐regulation of ADAM metallopeptidase with thrombospondin type 1 motif 4 (ADAMTS‐4), a secreted proteinase that regulates matrix degradation, was observed in smooth muscle cells (SMCs) of aortic tunica media, which was inhibited by miR‐126a‐5p. Dual‐luciferase results demonstrated ADAMTS‐4 as a new and valid target for miR‐126a‐5p. In vitro, human aortic SMCs (hASMCs) were stimulated by Ang II. Gain‐ and loss‐of‐function experiments further confirmed that miR‐126‐5p prevented Ang II‐induced ECM degradation, and reduced ADAMTS‐4 expression in hASMCs. In summary, our work demonstrates that miR‐126a‐5p limits experimental AAA formation and reduces ADAMTS‐4 expression in abdominal aortas.