Trends in Endocrinology & Metabolism
ReviewProinflammation: the key to arterial aging
Section snippets
Chronic inflammation and arterial aging
The demographics of modern society predict an exponential increase in the number of older persons in the future that could produce an epidemic of chronic arterial hypertension and atherosclerosis 1, 2, 3, 4, 5, 6. Central arterial aging is a hallmark of systems aging, and can be viewed as the failure of key signaling pathways to execute crucial functions [5]. These aging-related changes in the molecular and cellular functions of key signaling systems facilitate adverse central arterial
Proinflammatory signaling molecules within the aged arterial wall
The chronic proinflammatory profile within aged central arteries is characterized by alterations in major signaling cascades that include the renin/Ang II, the aldosterone/mineralocorticoid receptor (Aldo/MR) systems, and the endothelin-1 (ET-1)/endothelin-1 receptor A (ETA) system (Figure 1). The expression and/or activity of several proinflammatory transcription factors that lie downstream of these pathways are increased, whereas levels of protective factors are reduced (Figure 1). As a
Ang II and its receptors
The renin/angiotensin system was initially recognized as a potent vasoconstriction system. The proinflammatory profile of the Ang II signaling cascade plays a dominant role in the process of adverse arterial remodeling with aging in numerous species including humans (Table 1) 2, 3, 4, 5, 6. The transcription, translation, and activity of the angiotensin-converting enzyme-1 (ACE-1) markedly increase within both endothelial cells (ECs) and VSMCs with aging 7, 8, 9, 10. Additionally, expression of
Transcription factors involved in inflammation
The leading inflammatory triggers Ang II, Aldo, and ET-1 increase the activation of inflammatory transcription factors within the arterial wall, with aging (Figure 1). Elevated Ets-1 activity is closely associated with increased transcription of ET-1, monocyte chemoattractant protein-1 (MCP-1), transforming growth factor β1 (TGF-β1), and MMP-2 within the old arterial wall 16, 19. These proinflammatory triggers also increase the activation of the key inflammatory marker nuclear factor-κB, thus
Milk fat globule EGF-8 (MFG-E8) and integrins
A high-throughput proteomic screening identified MFG-E8, a cell adhesion protein, as a novel biomarker of aging arterial walls 12, 23, 24. Importantly, MFG-E8 is a key molecule for the pathogenesis of chronic arterial inflammation [24]. Levels of arterial MFG-E8 and its degradation fragment, medin, both increase and accumulate in the aorta with aging 12, 23, 24, 25. MFG-E8 is induced by Ang II and itself induces the expression of MCP-1 in VSMCs within the old rat aortic wall [12]. This places
Proinflammatory signals drive the phenotypic shift of vascular cells in the aging arterial wall
Chronic infusion of a physiologically relevant dose of Ang II to young rats increases activity of molecules that comprise the proinflammation profile, for example, MMP-2, MCP-1, calpain-1, TGF-β1, and NADPH oxidase 11, 13, 28. ACE inhibition and AT1 blockade, beginning at an early age, markedly inhibit the proinflammatory molecules and delays the progression of age-associated aortic remodeling 9, 10, 34. The combined proinflammation within arterial wall cells and matrix consequently drives
Endothelial cells
ECs, the frontline cells of the arterial wall, rest on the basement membrane and shoulder the component of the proinflammatory burden that originates within the circulation. The Ang II, MCP-1, and MFG-E8 inflammatory load is increased in the old endothelia 7, 11, 12, 30. This age-associated proinflammation may enhance ROS generation, which damages endothelial mitochondrial DNA and interferes with the mitochondrial life cycle 2, 3, 4, 5, 6, 21, 35. These responses initiate and promote EC
Vascular smooth muscle cells
Old VSMCs become stiffened and develop heterogeneous phenotypes within the arterial wall, with some cells functioning as ‘pluripotent cells’, similar to the phenotypic shifts of VSMCs also observed in hypertension, restenosis, and atherosclerosis, or in cell culture 2, 3, 4, 5, 6, 37, 38, 39. Concurrent VSMC proinflammatory secretion, senescence, proliferation, migration, and ECM deposition are characteristic features of arterial aging.
MMP inhibition, elastin fragmentation, and ECM deposition
Chronic administration of a broad-spectrum MMP inhibitor, PD166739, markedly blunts the age-associated increases in aortic gelatinase and interstitial collagenase activity, and reduces the elastic fiber degeneration, collagen deposition, MCP-1 expression, TGF-β1 activation, and SMAD-2/3 phosphorylation [16]. Interestingly, MMP inhibition also substantially diminishes pro-ET-1 activation and downregulates Ets-1 expression [16].
MFG-E8 and amyloidosis
Increased amyloid deposition is a characteristic of the aged arterial
Concluding remarks and future perspectives
A chronic increase in production of inflammatory signals is the key to age-associated adverse arterial structural remodeling, including diffuse intimal-medial thickening, increased stiffening and VSMC migration/proliferation/senescence. Under the microscope, the aged artery is characterized by the disruption of the endothelium, ECM deposition, elastin fracture, and matrix calcification/amyloidization/glycation. These adverse arterial cellular and molecular events are recapitulated in
Acknowledgments
This research was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health.
Glossary
- Age-associated arterial secretory phenotype (AAASP)
- a hostile extracellular microenvironment enriched with the secretion of proinflammatory molecules such as MCP-1 from old vascular cells, which share features of the fibroblast senescence-associated secretory phenotype (SASP).
- Aldosterone
- a steroid hormone and ligand for MR. It plays a central role in the regulation of blood pressure. Dysregulated aldosterone (and MR) in the heart and blood vessels negatively affects the cardiovascular system.
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