The Focal Adhesion: A Regulated Component of Aortic Stiffness

Robert Saphirstein,Yuan Gao,Kathleen Morgan,Susanne Vetterkind,Mikkel Jensen,Cynthia Gallant,Jeffrey Moore

doi:10.1096/fasebj.27.1_supplement.922.9

Abstract

Increased aortic stiffness is a known predictor and cause of cardiovascular disease, but much remains unknown about the sources and mechanisms of aortic stiffness. We tested the hypothesis that the focal adhesions (FAs) connecting vascular smooth muscle cells (VSMCs) to the matrix in the aortic wall are a dynamically regulated component of aortic stiffness. First, we used magnetic tweezers to measure cortical stiffness in A7r5 aortic VSMCs. Lysophosphatidic acid (LPA), an activator of myosin that increases cell contractility, increased cortical stiffness. A small molecule inhibitor of Src‐dependent FA recycling, PP2, significantly inhibited LPA‐induced increases in cortical stiffness, as well as tension‐induced increases in FA size. To extend these findings to the tissue level, we monitored mouse aorta ring stiffness with small sinusoidal length oscillations. The alpha‐agonist phenylephrine, which also increases myosin activation and contractility, increased tissue stress and stiffness in a PP2‐attenuated manner. Phosphotyrosine screening confirmed that the effect of PP2 in vascular tissue involves FA proteins. These data suggest that the transfer of VSMC actomyosin‐generated stress and stiffness to the aortic wall during contractile stimulation depends on FAs. Thus, we identify, for the first time, the FA of the VSMC as a significant subcellular regulator of aortic stiffness. Support: NIH P01 86655

Highlights

Normal cardiovascular function depends on the biomechanical properties of blood vessels, and changes in these properties are characteristic of disease
We examine the mechanical properties of blood vessels across multiple length scales and identify, for the first time, the Src-FAK signaling complex of focal adhesions (FAs) of the non-migratory, non-proliferating vascular smooth muscle cells (VSMCs) embedded in the blood vessel wall as a significant regulator of aortic stiffness
VSMC Cortical Stiffness is Modulated by FAs and Contractile Activation

Summary

Introduction

Normal cardiovascular function depends on the biomechanical properties of blood vessels, and changes in these properties are characteristic of disease. Increased aortic stiffness precedes and predicts for the development of hypertension and subsequent negative cardiovascular outcomes, including myocardial infarction, stroke, and heart disease [1,2]. The mechanical properties of a blood vessel, like any material or tissue, are determined by its components and their organization. The stiffness of vascular tissue can be derived from the composition of the extracellular matrix (ECM) and the cells in the tissue, the organization of the matrix and cells, and the connections that link these components (cell-matrix and cell-cell contacts). The prevailing view is that the ECM is the principal determinant of vascular stiffness [3]; the extent to which other tissue components contribute is unclear

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