Angiotensin II activates matrix metalloproteinase type II and mimics age-associated carotid arterial remodeling in young rats.
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-beta1 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 AT1 receptor antagonist Losartan inhibited these effects. The alpha-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-beta1, collagen, and VSMCs are central to the arterial remodeling that accompanies advancing age.
Wang
Mingyi
M
Laboratory of Cardiovascular Sciences, Gerontology Research Center, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Dr., 3-B-03, Baltimore, MD 21224-6825, USA.
Zhang
Jing
J
Spinetti
Gaia
G
Jiang
Li-Qun
LQ
Monticone
Robert
R
Zhao
Di
D
Cheng
Linda
L
Krawczyk
Melissa
M
Talan
Mark
M
Pintus
Gianfranco
G
Lakatta
Edward G
EG
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000375:Aging; D000804:Angiotensin II / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure; D015153:Blotting, Western; D002339:Carotid Arteries / Q000737:chemistry / Q000473:pathology*; D003094:Collagen / Q000032:analysis; D004151:Dipeptides / Q000494:pharmacology; D007150:Immunohistochemistry; D019808:Losartan / Q000494:pharmacology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000473:pathology; D009924:Organ Culture Techniques; D010656:Phenylephrine / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000032:analysis; D017539:Tunica Intima / Q000737:chemistry / Q000473:pathology; D014662:Vasoconstrictor Agents / Q000008:administration & dosage / Q000494:pharmacology
D000316:Adrenergic alpha-Agonists; D000959:Antihypertensive Agents; D004151:Dipeptides; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D011480:Protease Inhibitors; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D010656:Phenylephrine; D003094:Collagen; D020778:Matrix Metalloproteinase 2; D019808:Losartan