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A new twist to the primitive mechanical fate identifies an aged‐associated TGFβ1 nexus in vascular smooth muscle cells
Author(s) -
Zhu Wanqu,
Isak Abraham,
Monticone Robert E,
Wang Mingyi,
Lakatta Edward G,
An Steven S
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1300.3
Subject(s) - vascular smooth muscle , extracellular matrix , arterial stiffness , receptor , microbiology and biotechnology , internal elastic lamina , biology , medicine , endocrinology , chemistry , artery , smooth muscle , blood pressure
Central arterial stiffening is an independent predictor of cardiovascular morbidity and mortality in the U.S., and is adversely associated with advancing age. The transgression of age‐associated arterial stiffening is classically defined by pro‐inflammatory remodeling of the central arteries, culminating in altered deposition of extracellular matrix (ECM) and hyperplastic changes within the vascular smooth muscle (VSM) layer. Surprisingly, our understanding of age‐associated mechanical changes in the VSM compartment is largely unclear, and genetic/epigenetic nexus remains elusive. Here we adapted Fourier transform traction microscopy and magnetic twisting cytometry for the single‐cell analyses on the identity and state of mechanical properties of individual VSM cells isolated from the central aorta of young (8 months) vs. old (30 months) Fisher 344 cross‐bred Brown Norway rats. Compared with young VSM cells, old VSM cells were bigger in size and spontaneously exercised greater traction stress upon tuned elastic matrix. Old VSM cells also exhibited higher cytoskeletal (CSK) stiffness that is long‐lived in culture and, in the absence of inflammatory mediators, persistent across a wide range of matrix rigidities in a pathophysiologic spectrum. Moreover, Old VSM cells expressed higher levels of the latent TGFβ1 and showed intrinsically active TGFβ1 signaling. On the one hand, exogenous addition of TGFβ1 appreciably increased CSK stiffness in young, but not in old VSM cells. On the other, GW788388 and A8301, pharmacological inhibitors of TGFβ1 receptors, decreased the phosphorylation of Smad2/3 and normalized in turn the stiffness of old VSM cells in a dose‐dependent manner. Taken together, our findings demonstrate an age‐associated VSM contraction mechanophenotype that is independent of immune inflammatory responses, and provide a nodal point for potential therapeutics to rejuvenate and mitigate the central arterial stiffening. Support or Funding Information NIH R01 HL107361