Abstract
BackgroundAmong older adults, arterial aging is the major factor contributing to increased risk for cardiovascular disease–related morbidity and mortality. The chronic vascular inflammation that accompanies aging causes diffuse intimal–medial thickening of the arterial wall, thus increasing the vulnerability of aged vessels to vascular insults. Milk fat globule–epidermal growth factor 8 (MFG-E8) is a biomarker for aging arteries. This integrin-binding glycoprotein, induced by angiotensin II, facilitates vascular smooth muscle cell (VSMC) proliferation and invasion in aging vasculatures. This study investigated whether MFG-E8 directly mediates the initial inflammatory responses in aged arteries or VSMCs.MethodsA model of neointimal hyperplasia was induced in the common carotid artery (CCA) of aged mice to exacerbate age-associated vascular remodeling. Recombinant MFG-E8 (rMFG-E8) was administered to the injured artery using Pluronic gel to accentuate the effect on age-related vascular pathophysiology. The MFG-E8 level, leukocyte infiltration, and proinflammatory cell adhesion molecule (CAM) expression in the arterial wall were evaluated through immunohistochemistry. By using immunofluorescence and immunoblotting, the activation of the critical proinflammatory transcription factor nuclear factor (NF)-κB in the injured CCAs was analyzed. Immunofluorescence, immunoblotting, and quantitative real-time polymerase chain reaction were conducted using VSMCs isolated from the aortas of young and aged mice to assess NF-κB nuclear translocation, NF-κB-dependent gene expression, and cell proliferation. The extent of intimal–medial thickening in the injured vessels was analyzed morphometrically. Finally, Transwell migration assay was used to examine VSMC migration.ResultsEndogenous MFG-E8 expression in aged CCAs was significantly induced by ligation injury. Aged CCAs treated with rMFG-E8 exhibited increased leukocyte extravasation, CAM expression, and considerably increased NF-κB activation induced by rMFG-E8 in the ligated vessels. Exposure of early passage VSMCs from aged aortas to rMFG-E8 substantially increased NF-κB activation, proinflammatory gene expression, and cell proliferation. However, rMFG-E8 attenuated VSMC migration.ConclusionsMFG-E8 promoted the proinflammatory phenotypic shift of aged VSMCs and arteries, rendering the vasculature prone to vascular diseases. MFG-E8 may constitute a novel therapeutic target for retarding the aging processes in such vessels.
Highlights
Among older adults, arterial aging is the major factor contributing to increased risk for cardiovascular disease–related morbidity and mortality
The microenvironment enriched with inflammatory profiles subsequently induces the phenotypic shift of vascular smooth muscle cell (VSMC) from the contractile to synthetic type, which is characterized by the attenuated expression of SMC-specific contractile proteins along with increased proliferation of VSMCs, migration from the media to the intima, and secretion of additional proinflammatory cytokines, chemokines, extracellular matrix (ECM) proteins, and cell adhesion molecules (CAMs), such as monocyte chemotactic protein (MCP)-1, matrix metalloproteinase (MMP)-2 and − 9, collagen, intercellular adhesion molecule (ICAM)-1, and vascular CAM (VCAM)-1 [5, 15,16,17,18]
We investigated whether exogenous application of Recombinant MFG-E8 (rMFG-E8) to the injured common carotid artery (CCA) of aged mice exacerbates leukocyte extravasation and increases Intercellular adhesion molecule-1 (ICAM-1) and Vascular adhesion molecule-1 (VCAM-1) expression
Summary
Arterial aging is the major factor contributing to increased risk for cardiovascular disease–related morbidity and mortality. Milk fat globule–epidermal growth factor 8 (MFG-E8) is a biomarker for aging arteries This integrin-binding glycoprotein, induced by angiotensin II, facilitates vascular smooth muscle cell (VSMC) proliferation and invasion in aging vasculatures. This study investigated whether MFG-E8 directly mediates the initial inflammatory responses in aged arteries or VSMCs. Arterial aging is a major factor contributing to increases in cardiovascular disease–related morbidity and mortality [1,2,3,4,5]. Accumulating evidence suggests that these age-associated structural and functional alterations in the cells and extracellular matrix (ECM) of the vascular wall are attributable to chronic low-grade arterial inflammation driven by the enhanced angiotensin II (Ang II) signaling cascades that accompany advancing age [3, 7,8,9,10]. Targeting molecules involved in the Ang II–mediated signaling cascades in the vascular walls has therapeutic potential because it may attenuate age-associated chronic inflammation and retard aging processes in the vessels
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