Matrix Metalloproteinases Promote Arterial Remodeling in Aging, Hypertension, and Atherosclerosis

Wang, Mingyi; Kim, Soo Hyuk; Monticone, Robert E.; Lakatta, Edward G.

doi:10.1161/hypertensionaha.114.03618

Cited by 158 publications

(127 citation statements)

References 75 publications

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“…These last include intimal-medial thickening, fibrosis, calcification, and aneurysms, associated with reduction in endothelial-dependent vasodilatation and increased stiffness. Among AAASP components, the main contributors to aorta aging and remodeling are MMP-9 and -2, which degrade collagen, elastin, and other ECM molecules, resulting in increased DAMPs [72,73]. Their relevance in vascular aging has been confirmed by MMP inhibition studies.…”

Section: Structural and Functional Features Of The Aorta In Physiologmentioning

confidence: 99%

Toll-like receptor-4 signaling pathway in aorta aging and diseases: “its double nature”

Balistreri

Ruvolo

Lio

et al. 2017

Journal of Molecular and Cellular Cardiology

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Section: Structural and Functional Features Of The Aorta In Physiologmentioning

confidence: 99%

Toll-like receptor-4 signaling pathway in aorta aging and diseases: “its double nature”

Balistreri

Ruvolo

Lio

et al. 2017

Journal of Molecular and Cellular Cardiology

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“…MMP2 potently degrades elastin fibers and various types of degenerated collagen 1, 2. Gelatin zymography demonstrated that activated aortic gelatinases, including MMP 2/9 (green) in situ were increased in the old AL versus young AL aortae (Figure 6, upper panels), and that this age effect was substantially reduced in CR rats (Figure 6, upper right panel).…”

Section: Resultsmentioning

confidence: 98%

“…PDGF‐BB is not only a potent mitogen, but also a strong chemoattractant of VSMCs, creating a permissive tissue microenvironment for VSMC migration and invasion, promoting formation of a thickened intima in vivo 1, 2, 3, 8, 41, 42. Prior findings indicate that PDGF‐BB treatment induces invasion and migration of old VSMCs in vitro 8, 9.…”

Section: Discussionmentioning

confidence: 97%

“…With advancing age, adverse arterial remodeling occurs due to an increase in the proinflammation 1, 2, 31. Intimal thickening, collagen deposition, and elastin fragmentation are reliable indications of adverse arterial remodeling, which are closely associated with an increase in the prevalence and severity of age‐associated quintessential cardiovascular disease such as atherosclerosis due to either a reduction of threshold or an enhancement of susceptibility to hostile stimuli, for example, hyperlipidemia 1, 3, 31.…”

Section: Discussionmentioning

confidence: 99%

“…Aging exponentially increases the incidence of morbidity and mortality of quintessential cardiovascular disease mainly due to arterial wall proinflammatory phenotypic shifts at the molecular, cellular, and tissue levels 1, 2, 3. Increases in the local arterial wall proinflammatory molecules, platelet‐derived growth factor (PDGF), matrix metalloproteinase type II (MMP2) and transforming growth factor beta 1 (TGF‐β1), promote cellular and matrix phenotypic shifts that contribute to aortic wall thickening and stiffening that accompany advancing age in mammals, a prominent arterial phenotype of biological aging 4, 5, 6, 7, 8, 9.…”

mentioning

confidence: 99%

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

Wang

Zhang

Zhu

et al. 2018

JAHA

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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.

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Stiffening Matrix Induces Age‐Mediated Microvascular Phenotype Through Increased Cell Contractility and Destabilization of Adherens Junctions

et al. 2022

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Aging is a major risk factor in microvascular dysfunction and disease development, but the underlying mechanism remains largely unknown. As a result, age‐mediated changes in the mechanical properties of tissue collagen have gained interest as drivers of endothelial cell (EC) dysfunction. 3D culture models that mimic age‐mediated changes in the microvasculature can facilitate mechanistic understanding. A fibrillar hydrogel capable of changing its stiffness after forming microvascular networks is established. This hydrogel model is used to form vascular networks from induced pluripotent stem cells under soft conditions that mimic young tissue mechanics. Then matrix stiffness is gradually increased, thus exposing the vascular networks to the aging‐mimicry process in vitro. It is found that upon dynamic matrix stiffening, EC contractility is increased, resulting in the activation of focal adhesion kinase and subsequent dissociation of β ‐catenin from VE‐Cadherin mediated adherens junctions, leading to the abruption of the vascular networks. Inhibiting cell contractility impedes the dissociation of β ‐catenin, thereby preventing the deconstruction of adherens junctions, thus partially rescuing the age‐mediated vascular phenotype. The findings provide the first direct evidence of matrix's dynamic mechano‐changes in compromising microvasculature with aging and highlight the importance of hydrogel systems to study tissue‐level changes with aging in basic and translational studies.

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Matrix Metalloproteinases Promote Arterial Remodeling in Aging, Hypertension, and Atherosclerosis

Cited by 158 publications

References 75 publications

Toll-like receptor-4 signaling pathway in aorta aging and diseases: “its double nature”

Toll-like receptor-4 signaling pathway in aorta aging and diseases: “its double nature”

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

Stiffening Matrix Induces Age‐Mediated Microvascular Phenotype Through Increased Cell Contractility and Destabilization of Adherens Junctions

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