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, 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 the age-associated arterial proinflammation and its attendant increase in arterial pressure. Indeed, chronic administration of a broad-spectrum MMP inhibitor, PD166739, 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 TGF-β1;(5) a diminution in the activity of the profibrogenic signaling molecule SMAD-2/3 phosphorylation;(6) inhibition of proendothelin 1 activation;and (7) downregulation of expression of ets-1. Acute exposure of cultured vascular smooth muscle cells 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 vascular smooth muscle cells with an adenovirus harboring a full-length ets-1 cDNA increased activities of both TGF-β1and 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. Importantly, caloric restriction (CR), mimicking MMP inhibition, significantly improves arterial health. Immunostaining shows that 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 , MMP2 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, 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 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, recently we found that the vasorin gene encoding a 170-190 kDa secreted protein, markedly decreases in arterial wall and VSMC with aging. The vasorin highly binds to TGF-beta1 and has strong inhibitory ability of the interaction of TGF-beta1 and its type II receptor and markedly down-regulated MMP-2 activation, SMAD-2 phosphorylation, and collagen I in the aged VSMCs. 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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