Age-associated arterial remodeling involves arterial wall collagen deposition and elastin fragmentation as well as an increase in arterial pressure. This arterial remodeling is linked to proinflammatory signaling, including transforming growth factor-beta1 (TGF-β1), monocyte chemoattractant protein 1 (MCP-1), and proendothelin 1(pro-ET1), activated by extracellular matrix metalloproteinases (MMPs) and orchestrated, in part, by the transcriptional factor ets-1. We tested the hypothesis that inhibition of MMP activation can decelerate age-associated arterial proinflammation and its attendant increase in arterial pressure. Indeed, chronic administration of a broad-spectrum MMP inhibitor, PD166793, via a daily gavage, to 16-month-old rats for 8 months markedly blunted the expected age-associated increases in arterial pressure. This was accompanied by the following: (1) inhibition of the age-associated increases in aortic gelatinase and interstitial collagenase activity in situ; (2) preservation of the elastic fiber network integrity; (3) a reduction of collagen deposition; (4) a reduction of MCP-1 and TGF-β1 activity; (5) a diminution in the activity of the profibrogenic signaling molecule SMAD-2/3 phosphorylation; (6) inhibition of pro-ET1 activation; and (7) downregulation of expression of ets-1. Acute exposure of cultured vascular smooth muscle cells (VSMC) in vitro to proendothelin 1 increased both the transcription and translation of ets-1, and these effects were markedly reduced by MMP inhibition. Furthermore, infection of VSMC with an adenovirus harboring a full-length ets-1 cDNA increased activities of both TGF-β1 and MCP-1. Collectively, our results indicate that MMP inhibition retards age-associated arterial proinflammatory signaling, and this is accompanied by preservation of intact elastin fibers, a reduction in collagen, and blunting of an age-associated increase in blood pressure. Caloric restriction (CR), mimicking MMP inhibition, significantly improves arterial health. Immunostaining shows that the intimal VSMC number was increased in old compared to young diet ad libitum rats (AL), but was substantially reduced in the CR rat with aging. The intima-medial collagen deposition was increased, and the elastin fraction was decreased in the old AL rat. Impressively, aortic collagen and elastin fibers did not significantly change in the CR rat during aging. Notably, age enhanced in situ , MMP-2 and MCP-1 activation within the aortic wall in the AL rat, but these were blunted in the aorta of the old CR rats. Additionally, a potent pro-fibrogenic cytokine TGF-β1, a product of MMP-2 cleavage, and its downstream signaling molecule, p-SMAD-2, were enhanced in old compared to young AL rats, but CR reduced this effect. The intima-media gradient of a potent chemo-attractant, platelet derived growth factor (PDGF) was increased in old compared to young AL rats, but this was attenuated in CR rats. In addition, CR decreased early passage VSMC invasive capability in vitro in response to PDGF-BB, both in young (26%) and old (15%). Interestingly, CR substantially decreased MCP-1 expression in early passage VSMC compared to cells from AL rats. In summary, CR, like an MMP inhibitor, retards age-associated arterial restructuring in rats, at least in part, via reduction of MMP2, MCP-1, and TGF-β1 activation, the intima-media PDGF gradient, and VSMC invasive capability. Notably, we recently found that the vasorin gene encoding a 170-190 kDa secreted protein markedly decreases in the arterial wall and VSMC with aging. The vasorin highly binds to TGF-β1 and has a strong inhibitory ability on the interaction of TGF-β1 and its type II receptor and markedly down-regulated MMP-2 activation, SMAD-2/3 phosphorylation, and collagen I in VSMC. In vivo, transcription and translation of vasorin are markedly decreased within the aortic walls in old (30 mo) vs. young (8 mo) FXBN rats. In vitro, levels of vasorin protein in or secreted by primary cultured early passage VSMC from old aortae are substantially reduced compared to those of young cells. Furthermore, co-immunoprecipitation reveals that interaction of VSMC vasorin and TGF-β1 is significantly decreased with aging. Exposure of young VSMC to Ang II mimics increased p-SMAD-2/3 and collagen type I production in old cells or vasorin gene silenced young cells. These effects are abolished by an Ang II type I receptor (AT1) antagonist, Losartan, or by vasorin similar to overexpression of the vasorin gene in old VSMCs. Old VSMC exposure to Losartan markedly reduces p-SMAD2/3 and collagen production. Furthermore, overexpression of vasorin or exogenous vasorin treatment of young VSMCs inactivates and substantially inhibits the invasive proliferation capacity with aging, accompanied by an inactivation of MMP-2. In addition, compared to those from age-matched wild type mice, the deficiency of the TGF-β1 signal enhances phosphorylation of p-SMAD2/3 and collagen deposition. This is accompanied by an increase in proliferation cell nuclear antigen (PCNA) and cyclin-dependent kinase 4 (CDK4) observed in the adult (5-6 mo) vasorin knockout mouse arterial wall and myocardial interstitial space. These findings suggest that vasorin is a potential novel molecule to retard arterial VSMC inflammation with aging.
| Pintus, Gianfranco; Giordo, Roberta; Wang, Yushi et al. (2018) Reduced vasorin enhances angiotensin II signaling within the aging arterial wall. Oncotarget 9:27117-27132 |
| Wang, Mingyi; Monticone, Robert E; McGraw, Kimberly R (2018) Proinflammatory Arterial Stiffness Syndrome: A Signature of Large Arterial Aging. J Vasc Res 55:210-223 |
| Zhu, Wanqu; Kim, Byoung Choul; Wang, Mingyi et al. (2018) TGF?1 reinforces arterial aging in the vascular smooth muscle cell through a long-range regulation of the cytoskeletal stiffness. Sci Rep 8:2668 |
| AlGhatrif, Majd; Wang, Mingyi; Fedorova, Olga V et al. (2017) The Pressure of Aging. Med Clin North Am 101:81-101 |
| Wang, Mingyi; Kim, Soo Hyuk; Monticone, Robert E et al. (2015) Matrix metalloproteinases promote arterial remodeling in aging, hypertension, and atherosclerosis. Hypertension 65:698-703 |
| Wang, Mingyi; Monticone, Robert E; Lakatta, Edward G (2014) Proinflammation of aging central arteries: a mini-review. Gerontology 60:519-29 |
| Wang, Mingyi; Jiang, Liqun; Monticone, Robert E et al. (2014) Proinflammation: the key to arterial aging. Trends Endocrinol Metab 25:72-9 |
| Wang, Mingyi; Fu, Zongming; Wu, James et al. (2012) MFG-E8 activates proliferation of vascular smooth muscle cells via integrin signaling. Aging Cell 11:500-8 |
| Wang, Mingyi; Zhang, Jing; Telljohann, Richard et al. (2012) Chronic matrix metalloproteinase inhibition retards age-associated arterial proinflammation and increase in blood pressure. Hypertension 60:459-66 |
| Wang, Mingyi; Monticone, Robert E; Lakatta, Edward G (2010) Arterial aging: a journey into subclinical arterial disease. Curr Opin Nephrol Hypertens 19:201-7 |
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