Matrix metalloproteinase 2 activation of transforming growth factor-beta1 (TGF-beta1) and TGF-beta1-type II receptor signaling within the aged arterial wall.
OBJECTIVE
To study matrix metalloproteinase 2 (MMP-2) effects on transforming growth factor-beta1 (TGF-beta1) activation status and downstream signaling during arterial aging.


RESULTS
Western blotting and immunostaining showed that latent and activated TGF-beta1 are markedly increased within the aorta of aged Fisher 344 cross-bred Brown Norway (30 months of age) rats compared with adult (8 months of age) rats. Aortic TGF-beta1-type II receptor (TbetaRII), its downstream molecules p-similar to mad-mother against decapentaplegic (SMAD)2/3 and SMAD4, fibronectin, and collagen also increased with age. Moreover, TGF-beta1 staining is colocalized with that of activated MMP-2 within the aged arterial wall and vascular smooth muscle cell (VSMC) in vitro, and this physical association was confirmed by coimmunoprecipitation. Incubation of young aortic rings ex vivo or VSMCs in vitro with activated MMP-2 enhanced active TGF-beta1, collagen, and fibronectin expression to the level of untreated old counterparts, and this effect was abolished via inhibitors of MMP-2. Interestingly, in old untreated rings or VSMCs, the increased TGF-beta1, fibronectin, and collagen were also substantially reduced by inhibition of MMP-2.


CONCLUSIONS
Active TGF-beta1, its receptor, and receptor-mediated signaling increase within the aortic wall with aging. TGF-beta1 activation is dependent, in part at least, by a concomitant age-associated increase in MMP-2 activity. Thus, MMP-2-activated TGF-beta1, and subsequently TbetaRII signaling, is a novel molecular mechanism for arterial aging.
Wang
Mingyi
M
Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging/NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224-6825, USA. mingyiw@grc.nia.nih.gov
Zhao
Di
D
Spinetti
Gaia
G
Zhang
Jing
J
Jiang
Li-Qun
LQ
Pintus
Gianfranco
G
Monticone
Robert
R
Lakatta
Edward G
EG
D000375:Aging / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000502:physiology*; D015415:Biomarkers / Q000378:metabolism; D003094:Collagen / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000378:metabolism; D005353:Fibronectins / Q000096:biosynthesis; D020778:Matrix Metalloproteinase 2 / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D051785:Smad Proteins / Q000378:metabolism; D014018:Tissue Distribution; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1
D015415:Biomarkers; D005353:Fibronectins; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D003094:Collagen; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D020778:Matrix Metalloproteinase 2