Age-associated structural and functional remodeling of the arterial wall produces a productive environment for the initiation and progression of hypertension and atherosclerosis. Chronic aging stress induces low-grade proinflammatory signaling and causes cellular proinflammation in arterial walls, which triggers the structural phenotypic shifts characterized by endothelial dysfunction, diffuse intimal-medial thickening, and arterial stiffening. Microscopically, aged arteries exhibit an increase in arterial cell senescence, proliferation, invasion, matrix deposition, elastin fragmentation, calcification, and amyloidosis. These characteristic cellular and matrix alterations not only develop with aging but can also be induced in young animals under experimental proinflammatory stimulation. Interestingly, these changes can also be attenuated in old animals by reducing low-grade inflammatory signaling. Thus, mitigating age-associated proinflammation and arterial phenotype shifts is a potential approach to retard arterial aging and prevent the epidemic of hypertension and atherosclerosis in the elderly.

The glycosylated protein vasorin physically interacts with the transforming growth factor-beta1 (TGF-β1) and functionally attenuates its fibrogenic signaling in the vascular smooth muscle cells (VSMCs) of the arterial wall. Angiotensin II (Ang II) amplifies TGF-β1 activation in the VSMCs of the arterial wall with aging. In this study, we hypothesized that a reduced expression of the protein vasorin plays a contributory role in magnifying Ang II-associated fibrogenic signaling in the VSMCs of the arterial wall with aging. The current study shows that vasorin mRNA and protein expression were significantly decreased both in aortic wall and VSMCs from old (30 mo) vs. young (8 mo) FXBN rats. Exposing young VSMCs to Ang II reduced vasorin protein expression to the levels of old untreated cells while treating old VSMCs with the Ang II type AT1 receptor antagonist Losartan upregulated vasorin protein expression up to the levels of young. The physical interaction between vasorin and TGF-β1 was significantly decreased in old vs. young VSMCs. Further, exposing young VSMCs to Ang II increased the levels of matrix metalloproteinase type II (MMP-2) activation and TGF-β1 downstream molecules p-SMAD-2/3 and collagen type I production up to the levels of old untreated VSMCs, and these effects were substantially inhibited by overexpressing vasorin. Administration of Ang II to young rats (8 mo) for 28 days via an osmotic minipump markedly reduced the expression of vasorin. Importantly, vasorin protein was effectively cleaved by activated MMP-2 both in vitro and in vivo. Administration of the MMP inhibitor, PD 166793, for 6 mo to young adult (18 mo) via a daily gavage markedly increased levels of vasorin in the aortic wall. Thus, reduced vasorin amplifies Ang II profibrotic signaling via an activation of MMP-2 in VSMCs within the aging arterial wall.

BackgroundAging exponentially increases the incidence of morbidity and mortality of quintessential cardiovascular disease mainly due to arterial proinflammatory shifts at the molecular, cellular, and tissue levels within the arterial wall. Calorie restriction (CR) in rats improves arterial function and extends both health span and life span. How CR affects the proinflammatory landscape of molecular, cellular, and tissue phenotypic shifts within the arterial wall in rats, however, remains to be elucidated.Methods and ResultsAortae were harvested from young (6‐month‐old) and old (24‐month‐old) Fischer 344 rats, fed ad libitum and a second group maintained on a 40% CR beginning at 1 month of age. Histopathologic and morphometric analysis of the arterial wall demonstrated that CR markedly reduced age‐associated intimal medial thickening, collagen deposition, and elastin fractionation/degradation within the arterial walls. Immunostaining/blotting showed that CR effectively prevented an age‐associated increase in the density of platelet‐derived growth factor, matrix metalloproteinase type II activity, and transforming growth factor beta 1 and its downstream signaling molecules, phospho‐mothers against decapentaplegic homolog‐2/3 (p‐SMAD‐2/3) in the arterial wall. In early passage cultured vascular smooth muscle cells isolated from AL and CR rat aortae, CR alleviated the age‐associated vascular smooth muscle cell phenotypic shifts, profibrogenic signaling, and migration/proliferation in response to platelet‐derived growth factor.Conclusions CR reduces matrix and cellular proinflammation associated with aging that occurs within the aortic wall and that are attributable to platelet‐derived growth factor signaling. Thus, CR reduces the platelet‐derived growth factor–associated signaling cascade, contributing to the postponement of biological aging and preservation of a more youthful aortic wall phenotype.

Aging is a major risk factor for the morbidity and mortality of quintessential cardiovascular diseases, such as hypertension and atherosclerosis, mainly due to arterial wall structural and functional adverse remodeling, such as intimal medial thickening (IMT) and stiffening. 1-5 The age-associated increase in collagen deposition within the arterial wall is known as arterial profibrosis; and the age-associated increase in sterile inflammation within the wall is known as arterial proinflammation. Proinflammation and profibrosis are the key molecular and cellular events in age-associated IMT and arterial stiffening. It is widely accepted that proinflammatory endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) are mainly responsible for age-associated adverse arterial cellular events; however, the consequence of proinflammation and profibrosis (predisposing collagen deposition) greatly affects the behavior of these cells adversely with a predominant impact on the age-associated arterial stiffening, which is not completely understood. 1-5 Aging increases the proinflammatory molecules angiotensin II (Ang II), milk fat globule-EGF8 (MFG-E8), calpain-1, monocyte chemoattractant protein 1 (MCP-1), non-phagocytic nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase), and

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Linking agricultural management tactics to quantifiable changes in soil health-related properties is a key objective for increasing adoption of the most favorable management practices. We used two long-term, no-till cropping studies to illustrate the variable patterns of response of soil structure indices and microbial activity to additional management tactics, including crop rotational diversity, residue management and cover cropping. We found that observable effects of management tactics on soil properties were often dependent on the current crop phase sampled, even though the treatments were well-established. In some cases, a single additional management tactic produced a response, two tactics each produced a response and sometimes there were interactions between tactics. However, importantly, we never observed a negative effect for any of the response variables when stacking soil health building practices in no-till cropping systems. The collective results from the two field studies illustrate that soil health improvements with stacking management tactics are not always simply additive and are affected by temporal relationships inherent to the treatments. We conclude that the implementation of multiple positive management tactics increases the likelihood that improvements in soil properties can be documented with one or more of the proxy measures for soil health.

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ObjectiveThe proinflammatory phenotypic shift of vascular smooth muscle cells (VSMCs) is closely linked to the elastolysis and calcification in the aging arterial wall. Degradation of tropoelastin (TPELN) is a key molecular event which often accompanies the proinflammatory phenotypic shift of VSMCs, arterial elastolysis and calcification with aging. Milk fat globule-EGF factor 8 (MFG-E8), secreted mainly from VSMCs, predominantly binds to degenerated elastin fibers, and alters VSMCs phenotypes. Here, we investigated how MFG-E8 proinflammatory signaling in the arterial wall, in vivo, and VSMCs, in vitro, affects arterial elastolysis and calcification with advancing age.Methods and ResultsIn vivo immunostaining and immunoblotting studies indicated that MFG-E8, elastic lamina breaks, and calcium-phosphorus products were markedly increased while intact TPELN (∼70Kda) protein was dramatically decreased in aortic walls or isolated aortic VSMCs harvested from old (30-month-old) vs. young (8-month-old) Fischer 344 × Brown Norway rats (FXBN). In vitro studies demonstrated that (1) treating either young or old VSMCs to recombinant human MFG-E8 (rhMFG-E8) for 24 hours significantly reduced intact TPLEN levels and this effect was reduced by SB203580, a p38 mitogen-activated protein kinase inhibitor; (2) activated MMP-2 levels were significantly increased in both young and old VSMCs treated with rhMFG-E8, and this activation was also inhibited by SB203580; (3) MMP-2 physically interacted with TPLEN and cleaved intact TPLEN from VSMCs; (4) downregulation of either MFG-E8 or MMP-2 in VSMCs via siRNA significantly increased the levels of intact TPELN; (5) rhMFG-E8 treatment markedly reduced contractile protein, smooth muscle 22-alpha, and anti-calcification protein, fetuin-A, levels in both young and old VSMCs, which were blocked by SB203580. Notably, MMP-2 activity, elastic laminae degeneration, and calcium deposits were significantly increased while fetuin-A levels are markedly decreased in old WT vs. MFG-E8 mice.ConclusionsTaken together, our current findings suggest that MFG-E8, via p38 signaling in VSMCs, promotes MMP-2-associated elastolysis and calcification in the aging arterial wall.