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TGF?1 reinforces arterial aging in the vascular smooth muscle cell through a long-range regulation of the cytoskeletal stiffness.

ABSTRACT: 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. This discrete mechanical response was long-lived in culture and persistent across a physiological range of matrix rigidity. Strikingly, the pro-fibrotic transforming growth factor ?1 (TGF?1) emerged as a specific modifier of age-associated VSM stiffening in vitro. TGF?1 reinforced the mechanical phenotype of arterial aging in VSM cells on multiple time and length scales through clustering of mechanosensitive ?5?1 and ?v?3 integrins. Taken together, these studies identify a novel nodal point for the long-range regulation of VSM stiffness and serve as a proof-of-concept that the broad-based inhibition of TGF?1 expression, or TGF?1 signal transduction in VSM, may be a useful therapeutic approach to mitigate the pathologic progression of central arterial wall stiffening associated with aging.

SUBMITTER: Zhu W

PROVIDER: S-EPMC5805716 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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

Zhu Wanqu W Kim Byoung Choul BC Wang Mingyi M Huang Jessie J Isak Abraham A Bexiga Natalia M NM Monticone Robert R Ha Taekjip T Lakatta Edward G EG An Steven S SS

Scientific reports 20180208 1

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. This discrete ...[more]

PMID: 29422510

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Project description: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.

Dataset Information

TGF?1 reinforces arterial aging in the vascular smooth muscle cell through a long-range regulation of the cytoskeletal stiffness.

Publications

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

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