Milk Fat Globule Epidermal Growth Factor VIII Fragment Medin in Age-Associated Arterial Adverse Remodeling and Arterial Disease.

Medin, a small 50-amino acid peptide, is an internal cleaved product from the second discoidin domain of milk fat globule epidermal growth factor VIII (MFG-E8) protein. Medin has been reported as the most common amylogenic protein in the upper part of the arterial system, including aortic, temporal, and cerebral arterial walls in the elderly. Medin has a high affinity to elastic fibers and is closely associated with arterial degenerative inflammation, elastic fiber fragmentation, calcification, and amyloidosis.

Inflammatory Role of Milk Fat Globule-Epidermal Growth Factor VIII in Age-Associated Arterial Remodeling.

Background Age-associated aortic remodeling includes a marked increase in intimal medial thickness (IMT), associated with signs of inflammation. Although aortic wall milk fat globule-epidermal growth factor VIII (MFG-E8) increases with age, and is associated with aortic inflammation, it is not known whether MFG-E8 is for the age-associated increase in aortic IMT. Here, we tested whether MFG-E8 is for the age-associated increase in aortic IMT.

Age-associated proinflammatory elastic fiber remodeling in large arteries.

Elastic fibers are the main components of the extracellular matrix of the large arterial wall. Elastic fiber remodeling is an intricate process of synthesis and degradation of the core elastin protein and microfibrils accompanied by the assembly and disassembly of accessory proteins. Age-related morphological, structural, and functional proinflammatory remodeling within the elastic fiber has a profound effect upon the integrity, elasticity, calcification, amyloidosis, and stiffness of the large arterial wall.

Proinflammation, profibrosis, and arterial aging.

Aging is a major risk factor for quintessential cardiovascular diseases, which are closely related to arterial proinflammation. The age-related alterations of the amount, distribution, and properties of the collagen fibers, such as cross-links and degradation in the arterial wall, are the major sequelae of proinflammation. In the aging arterial wall, collagen types I, II, and III are predominant,  and are mainly produced by stiffened vascular smooth muscle cells (VSMCs) governed by proinflammatory signaling, leading to profibrosis.

Discoidin domain Receptor 2: A determinant of metabolic syndrome-associated arterial fibrosis in non-human primates.

Collagen accumulation and remodeling in the vascular wall is a cardinal feature of vascular fibrosis that exacerbates the complications of hypertension, aging, diabetes and atherosclerosis. With no specific therapy available to date, identification of mechanisms underlying vascular fibrogenesis is an important clinical goal. Here, we tested the hypothesis that Discoidin Domain Receptor 2 (DDR2), a collagen-specific receptor tyrosine kinase, is a determinant of arterial fibrosis.

Calorie Restriction Curbs Proinflammation That Accompanies Arterial Aging, Preserving a Youthful Phenotype.

Background Aging 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.

Proinflammatory Arterial Stiffness Syndrome: A Signature of Large Arterial Aging.

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.

Reduced vasorin enhances angiotensin II signaling within the aging arterial wall.

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.

TGFβ1 reinforces arterial aging in the vascular smooth muscle cell through a long-range regulation of the cytoskeletal stiffness.

Here we report exquisitely distinct material properties of primary vascular smooth muscle (VSM) cells isolated from the thoracic aorta of adult (8 months) vs. aged (30 months) F344XBN rats. Individual VSM cells derived from the aged animals showed a tense internal network of the actin cytoskeleton (CSK), exhibiting increased stiffness (elastic) and frictional (loss) moduli than those derived from the adult animals over a wide frequency range of the imposed oscillatory deformation.

Proinflammation of aging central arteries: a mini-review.

Arterial aging is a cornerstone of organismal aging. The central arterial wall structurally and functionally remodels under chronic proinflammatory stress over a lifetime. The low-grade proinflammation that accompanies advancing age causes arterial wall thickening and stiffening.

Proinflammation: the key to arterial aging.

Arterial aging is the major contributing factor to increases in the incidence and prevalence of cardiovascular disease, due mainly to the presence of chronic, low-grade, 'sterile' arterial inflammation. Inflammatory signaling driven by the angiotensin II cascade perpetrates adverse age-associated arterial structural and functional remodeling. The aged artery is characterized by endothelial disruption, enhanced vascular smooth muscle cell (VMSC) migration and proliferation, extracellular matrix (ECM) deposition, elastin fracture, and matrix calcification/amyloidosis/glycation.

Calpain-1 regulation of matrix metalloproteinase 2 activity in vascular smooth muscle cells facilitates age-associated aortic wall calcification and fibrosis.

Age-associated central arterial wall stiffness is linked to extracellular matrix remodeling, including fibrosis and vascular calcification. Angiotensin II induces both matrix metalloproteinase 2 (MMP2) and calpain-1 expression and activity in the arterial wall. However, the role of calpain-1 in MMP2 activation and extracellular matrix remodeling remains unknown.

Chronic matrix metalloproteinase inhibition retards age-associated arterial proinflammation and increase in blood pressure.

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-β1, monocyte chemoattractant protein 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.

MFG-E8 activates proliferation of vascular smooth muscle cells via integrin signaling.

An accumulation of milk fat globule EGF-8 protein (MFG-E8) occurs within the context of arterial wall inflammatory remodeling during aging, hypertension, diabetes mellitus, or atherosclerosis. MFG-E8 induces VSMC invasion, but whether it affects VSMC proliferation, a salient feature of arterial inflammation, is unknown. Here, we show that in the rat arterial wall in vivo, PCNA and Ki67, markers of cell cycle activation, increase with age between 8 and 30 months.

Age-associated vascular oxidative stress, Nrf2 dysfunction, and NF-{kappa}B activation in the nonhuman primate Macaca mulatta.

Aging promotes oxidative stress in vascular endothelial and smooth muscle cells, which contribute to the development of cardiovascular diseases. NF-E2-related factor 2 (Nrf2) is a transcription factor, which is activated by reactive oxygen species in the vasculature of young animals, leading to adaptive upregulation of numerous reactive oxygen species detoxifying and antioxidant genes. The present study was designed to elucidate age-associated changes in the homeostatic role of Nrf2-driven free radical detoxification mechanisms in the vasculature of nonhuman primates.

A local proinflammatory signalling loop facilitates adverse age-associated arterial remodeling.

Background: The coincidence of vascular smooth muscle cells (VSMC) infiltration and collagen deposition within a diffusely thickened intima is a salient feature of central arterial wall inflammation that accompanies advancing age. However, the molecular mechanisms involved remain undefined.

Methodology/principal Findings: Immunostaining and immunoblotting of rat aortae demonstrate that a triad of proinflammatory molecules, MCP-1, TGF-β1, and MMP-2 increases within the aortic wall with aging.

Elevated mineralocorticoid receptor activity in aged rat vascular smooth muscle cells promotes a proinflammatory phenotype via extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase and epidermal growth factor receptor-dependent pathways.

Arterial aging is a predominant risk factor for the onset of cardiovascular diseases, such as hypertension, myocardial infarction, or stroke. Aging is associated with intravascular renin-angiotensin system activation, increased vascular stiffness, intima-media thickening, and a proinflammatory phenotype. Little is known about the influence of aldosterone on arterial aging.

Arterial aging: a journey into subclinical arterial disease.

Purpose Of Review: Age-associated arterial alterations in cells, matrix, and biomolecules are the foundation for the initiation and progression of cardiovascular diseases in older persons. This review focuses on the latest advances on the intertwining of aging and disease within the arterial wall at the cell and molecular levels.

Recent Findings: Endothelial dysfunction, vascular smooth muscle cell (VSMC) proliferation/invasion/secretion, matrix fragmentation, collagenization and glycation are characteristics of an age-associated arterial phenotype that creates a microenvironment enriched with reactive oxygen species (ROS) for the pathogenesis of arterial disease.

Milk fat globule protein epidermal growth factor-8: a pivotal relay element within the angiotensin II and monocyte chemoattractant protein-1 signaling cascade mediating vascular smooth muscle cells invasion.

Advancing age induces aortic wall thickening that results from the concerted effects of numerous signaling proteins, many of which have yet to be identified. To search for novel proteins associated with aortic wall thickening, we have performed a comprehensive quantitative proteomic study to analyze aortic proteins from young (8 months) and old (30 months) rats and identified 50 proteins that significantly change in abundance with aging. One novel protein, the milk fat globule protein epidermal growth factor 8 (MFG-E8), increases 2.

Increased aortic calpain-1 activity mediates age-associated angiotensin II signaling of vascular smooth muscle cells.

Background: Angiotensin II (Ang II) signaling, including matrix metalloproteinase type II (MMP2) activation, has been linked to an age-associated increase in migration capacity of vascular smooth muscle cells (VSMC), and to other proinflammatory features of arterial aging. Calpain-1 activation is required for MMP2 expression in fibroblasts and is induced in cardiomyocytes by Ang II. The consequences of engagement of calpain-1 with its substrates, however, in governing the age-associated proinflammatory status within the arterial wall, remains unknown.

Proinflammatory profile within the grossly normal aged human aortic wall.

Studies in animal models demonstrate that angiotensin II and its downstream signaling molecules, that is, matrix metalloproteinases and monocyte chemoattractant protein-1, increase within the diffusely thickened intima of central arteries with aging. Whether such age-related changes occur within the human arterial wall is unknown. We harvested "grossly normal thoracic aortas" from 5 young (20+/-3 years) and 5 old white males (65+/-6 years) at necropsy, after death from traumatic causes.

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.

Methods And 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.

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.