Angiotensin II Activates Matrix Metalloproteinase Type II and Mimics Age-Associated Carotid Arterial Remodeling in Young Rats

Abstract

Increased angiotensin II (Ang II), matrix metalloproteinase type II (MMP2), and sympathetic activity accompany age-associated arterial remodeling. To analyze this relationship, we infused a low subpressor dose of Ang II into young (8 months old) rats. This increased carotid arterial MMP2 transcription, translation, and activation, as well as transforming growth factor-␤1 activity and collagen deposition. A higher Ang II concentration, which increased arterial pressure to that of old (30 months old) untreated rats, produced carotid media thickening and intima infiltration by vascular smooth muscle cells (VSMCs). Ex vivo, Ang II increased MMP2 activity in carotid rings from young rats to that of untreated old rats. Ang II also increased the ability of early passage VSMCs from young rats to invade a synthetic basement membrane, similar to that of untreated VSMCs from old rats. The MMP inhibitor GM6001 and the AT 1 receptor antagonist Losartan inhibited these effects. The ␣-adrenoreceptor agonist phenylephrine increased arterial Ang II protein, causing MMP2 activation and intima and media thickening. Exposure of young VSMCs to phenylephrine in vitro increased Ang II protein and MMP2 activity to the levels of old VSMCs; Losartan abolished these effects. Thus, Ang II-induced effects on MMP2, transforming growth factor-␤1, collagen, and VSMCs are central to the arterial remodeling that accompanies advancing age. (Am J Pathol 2005,

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“…aneurysm), VR has been studied in various species including rats, rabbits, nonhuman primates, and humans, being an evolutionarily conserved process (see Table 3). The findings obtained have provided insights into the molecular and cellular mechanisms of aorta aging in humans [51][52][53][54][55][56][57][58][59][60]. Precisely, it has been shown that age-associated aorta VR is the result of a sterile inflammation, probably mediated by two supposed mechanisms: 1) infiltration of immune cells, that degrade tissues and release reactive or toxic molecules, causing DAMPs production [61]; 2) phenotypic changes in endothelial cells (ECs) and VSMCs evoked by altered and overload expression of stress and stretch signaling pathways, triggered by different stressors or damage tissue stimuli throughout life (i.e.…”

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“…[3][4][5][6] With advancing age, TGF-␤1, collagen, and FN increase within the arterial wall, predominantly within the intimal and adventitial layers, and are linked to the ageassociated increase in arterial stiffness. 1,2,[7][8][9] Subsequently, age-associated cross-linking of collagen attributable to nonenzymatic glycation/glycosylation reactions leads to a further loss of elasticity and increased stiffness. 10 The modifications of matrix proteins alter the niche of resident vascular cells, such as vascular endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), and their survival, migration, and proliferation capabilities.…”

Calorie Restriction Curbs Proinflammation That Accompanies Arterial Aging, Preserving a Youthful Phenotype

“…VSMC phenotypes can exhibit plasticity in response to modulation by the age‐associated alterations in the proinflammatory niche, characterized by a loss of contractility and abnormal proliferation and migration 7, 9, 27. These VSMC phenotypic shifts are driven by a coordinated repression/activation of contractile markers SM22α, α‐SMA, and myocardin 28, 29.…”

“…Zymography was performed according to modified protocols, as previously reported 5, 6, 7, 18. Sodium dodecyl sulfate polyacrylamide gel electrophoresis zymography was performed according to the manufacturer's protocol (ThermoFisher).…”

“…Increases in the local arterial wall proinflammatory molecules, platelet‐derived growth factor (PDGF), matrix metalloproteinase type II (MMP2) and transforming growth factor beta 1 (TGF‐β1), promote cellular and matrix phenotypic shifts that contribute to aortic wall thickening and stiffening that accompany advancing age in mammals, a prominent arterial phenotype of biological aging 4, 5, 6, 7, 8, 9. Interestingly, arterial proinflammatory conditions reduces the threshold or increases the susceptibility for pernicious inflammatory arterial events under hostile conditions such as hyperlipidemia 1, 10…”